Illness can impact a president’s ability to conduct the duties of office, but for most of U.S. history, protocol for what happens when a president got sick was minimal.

The Founding Fathers anticipated the need for a line of succession, and the Constitution says the vice president becomes acting president if the elected one dies, resigns or became debilitated. But it left out critical details, including who has the power to declare the president unfit to serve, when and how the president should return to office, and if the vice president should continue as president for the rest of the term or until a replacement was found.

It took the assassination of John F. Kennedy for Congress to pass the 25th Amendment laying out a clear protocol with the 25th Amendment for what happens if the president or vice president resigns, becomes incapacitated or disabled, or dies.

Congress attempted to address the confusion over what happens if a president becomes unfit while in office with a series of three succession acts. The first Presidential Succession Act was passed in February 1792, and said the Majority Leader of the House of Representatives and the President Pro Tempore of the Senate were next in the line of succession.

The next succession act of 1886 replaced the leaders of the Senate and House of Representatives with the presidential cabinet in order of rank, meaning the Secretary of State followed the Vice President in the line of succession. Lawmakers argued they would have a better executive skillset: At the time, no president pro tempore had ever served as president, while six former secretaries of state had been elected to that office.

The line of succession changed again on July 18, 1947, when President Harry Truman signed the Presidential Succession Act. It restored the 1792 rules, but switched their order: Since 1947, the line of succession for president of the United States goes from the Vice President to the Speaker of the House, then the President Pro Tempore of the Senate.

The passage of the 25th Amendment solidified the protocol for presidential succession. It was passed in the wake of the assassination of John F. Kennedy, when there was initial fear that Vice President Lyndon B. Johnson had also been injured. The 25th Amendment was signed into law by Johnson on February 23, 1967 and states, in part:

Section 1: If the President Dies or Resigns, the Vice President Becomes President

“In case of the removal of the President from office or of his death or resignation, the Vice President shall become President.”

Section 2: The President Can Nominate a New Vice President

“Whenever there is a vacancy in the office of the Vice President, the President shall nominate a Vice President who shall take office upon confirmation by a majority vote of both Houses of Congress.”

Section 3: If the President Is Ill, The Vice President Becomes Acting President

“Whenever the President transmits to the President pro tempore of the Senate and the Speaker of the House of Representatives his written declaration that he is unable to discharge the powers and duties of his office, and until he transmits to them a written declaration to the contrary, such powers and duties shall be discharged by the Vice President as Acting President.”

Section 4: If the President Is Declared Unfit to Serve, the Vice President Will Become Acting President

“Whenever the Vice President and a majority of either the principal officers of the executive departments or of such other body as Congress may by law provide, transmit to the President pro tempore of the Senate and the Speaker of the House of Representatives their written declaration that the President is unable to discharge the powers and duties of his office, the Vice President shall immediately assume the powers and duties of the office as Acting President.”

The third section of the 25th amendment has only been invoked three times in history: During Ronald Reagan’s surgery for colon cancer in 1985 and for George W. Bush’s colonoscopies in 2002 and 2007.

Reagan’s staff considered invoking the fourth section of the 25th amendment when the president began acting strangely in the wake of the Iran-Contra Scandal, but his chief of staff ultimately decided against it. Reagan’s Alzheimer’s diagnosis after he left office has led historians to speculate that he may have been experiencing early symptoms of the disease while serving as president.

Long before the passage and application of the 25th amendment, numerous presidents dealt with illness or medical conditions—some openly, others in secret—while serving in office.

The first president to fall seriously ill while in office was the nation's first president, George Washington. Two months into his first term, Washington underwent surgery for a tumor that required him to rest on his right side for six weeks. In his second year of office, Washington survived a bout of influenza that threatened his hearing and his sight, prompting him to write: “I have already had within less than a year, two severe attacks—the last worst than the first—a third more than probable will put me to sleep with my fathers; at what distance this may be I know not.”

Disease ran rampant in America’s early cities, and an outbreak of yellow fever in the summer of 1793 prompted Washington and the government to flee to the countryside. Washington survived, as he’d survive diphtheria, tuberculosis, smallpox, malaria, dysentery, quinsy, and carbuncle, along with many near-misses on the battlefield. He eventually died of a throat infection, but after he’d left office.

William Henry Harrison became the shortest-serving president when he died just 34 days into taking office from pneumonia he contracted on inauguration day. He was the first president to die while in office, meaning there was no precedent for Vice President John Tyler’s rise to power.

While Tyler was initially given the title “Vice President Acting President” by Congress, he sought a more permanent job title. Tyler moved into the White House and had himself sworn in as president, even giving an Inaugural Address.

In 1893, Grover Cleveland needed surgery to remove a cancerous tumor in his mouth. To avoid the attention of the press, he had the surgery performed on his friend’s yacht in Long Island Sound. He had a quarter of his upper palate entirely removed, was fitted with an implant, and went back to work. The public was none the wiser.

Woodrow Wilson nearly died of the 1918 flu pandemic during sensitive negotiations with world leaders at the Paris Peace Talks. With the flu decimating civilians and soldiers in World War I—20 million people eventually died from the disease worldwide—Wilson’s doctor lied, telling the press the President had caught a cold from the rain in Paris.

Wilson’s illness depleted him, and aides became worried it was hindering the president's ability to negotiate. Ultimately, Wilson relinquished his demands on French leader Georges Clemenceau, accepting the demilitarization of the Rhineland and French occupation of it for at least 15 years. The resulting Treaty of Versailles was so harsh on Germany that it contributed to the rise of Adolf Hitler and the outbreak of World War II.

It wouldn’t be the last time a doctor lied about Wilson’s condition: In 1919, he suffered a series of strokes that prompted his cabinet to suggest the vice president take over. First Lady Edith Wilson and the president’s doctor, Cary Grayson, refused.

The United States' longest-serving president, Franklin Delano Roosevelt, hid the severity of his polio from the American public, fearing he would be perceived as weak. He avoided using his wheelchair during appearances to “walk” with the aid of leg braces, a cane, and usually the arm of an advisor. The press was forbidden from taking pictures of him walking—an offense the Secret Service was tasked with preventing.

During Dwight D. Eisenhower’s years in office, he suffered a heart attack, was diagnosed with and underwent surgery for Crohn’s disease, and had a stroke. Concerned he wouldn’t recover, Eisenhower wrote a confidential letter to his vice president, Richard M. Nixon, telling him what to do in the event he didn’t regain his faculties.

In it, he named Nixon as the person responsible for determining whether or not Eisenhower could perform his presidential duties. The letter was not legal, and Nixon took over the duties of president only momentarily, once in 1955 after the president’s heart attack and again during his 1956 surgery.

The 25th Amendment was formally invoked for the first time on July 13, 1985, when President Ronald Reagan directed then-Vice President George H.W. Bush to perform his duties while he underwent surgery for colon cancer. Bush became acting president when Reagan was administered general anesthesia. After just under eight hours, Reagan notified the Senate that he was ready to resume his presidential duties.

During his two-term presidency, George W. Bush invoked the 25th Amendment twice. On June 29, 2002, Bush invoked Section 3 of the 25th Amendment prior to going under anesthesia for a colonoscopy and briefly made Vice President Dick Cheney the acting president. He did the same again when he had another colonoscopy in 2007.