Guiteau never manifested an interest in politics until 1872 when he became convinced that electioneering for a presidential candidate would result in a patronage position.  He did not have just any government job in mind, but the U.S. ministership to Chile.  He worked on Horace Greeley's campaign, but when the New York Tribune editor was unsuccessful, Guiteau turned to religion.  His Baptist church kicked him out in 1875 after his divorce, but the next fall he began attending revivals in Chicago led by Dwight Moody, one of the nation's leading evangelists.  Guiteau became an usher, and was allowed to address a meeting, until Moody intervened to stop his rambling sermon.  Undeterred, Guiteau studied religion on his own and wrote a Bible commentary.  His subsequent attempt at preaching was a dismal failure.

In 1880, Guiteau took up politics again.  He began hanging around Republican campaign headquarters in New York City, where he met Chester Arthur and other important Republicans, and was allowed to do minor tasks.  Although co-workers considered him strange, they treated him politely, which he interpreted incorrectly as respect.  On his own initiative, he wrote a campaign speech praising former president Grant, but when Garfield was nominated that summer, Guiteau simply replaced Grant's name with Garfield's.  

When electoral returns in the "October states" (which voted before the November election) indicated a Garfield victory, Guiteau began his letter writing campaign for a diplomatic mission.  He explained to the new president that he would soon be marrying a wealthy woman from a prominent New York Republican family (he had seen her once in church), and he would therefore be an excellent choice for minister to Vienna or Paris.

In early March 1881, two days after Garfield's presidential inauguration, Guiteau arrived in Washington with five dollars in his pocket and one extra shirt.  He took up residence at a boarding house, where the perceptive landlady placed him in an out-of-the-way room.  However, he still managed to bother the other residents, particularly Senator John Logan, an Illinois Republican, whom he badgered about the diplomatic appointment.  Guiteau began visiting the State Department, where he sought the intervention of the new secretary of state, James Blaine.  The future assassin also began visiting the White House, where he waited with numerous other office-seekers.

On May 13, Guiteau argued with White House ushers and was barred from returning.  The next day when he accosted Blaine on the street, the harassed secretary of state yelled at him, "Never speak to me again on the Paris consulship as long as you live!"  On May 16, a patronage battle between President Garfield and New York's senators, Roscoe Conkling and Thomas Platt, ended in the senators' surprise resignation.  Guiteau concluded that his campaign for a diplomatic post was thwarted by a conspiracy against the Stalwart wing of the Republican Party, represented by Conkling and Vice President Arthur.  On May 18, Guiteau further surmised that the solution was to rid the world of President Garfield, and that he was God's chosen instrument for that duty.

On Sunday, June 12, Guiteau followed the president to church, and decided that shooting him through a window on the following Sunday would be preferable to doing so inside the building.  The assassin revised his plans, however, when it was announced that Garfield would escort his ailing wife to the resort of Long Branch, New Jersey.  Guiteau decided to kill the president at the train station, but was deterred that Saturday morning, June 18, by the sight of the feeble Mrs. Garfield.  In the meantime, Guiteau visited the prison where he would be held, pronouncing it "excellent ... the best jail in America," and he revised his biblical commentary for posthumous publication.

The president returned to Washington on June 27, planning to depart for the summer on July 2.  Guiteau again trailed Garfield, deciding not to shoot the president at two opportunities.  Finally, on July 2, Guiteau believed that it was now or never.  The assassin arrived at the Baltimore and Potomac Depot at the corner of Pennsylvania Avenue and Sixth Street at 8:30 a.m.  He paced the floor nervously, and deposited two packages with a newsstand manager:  a letter to reporters explaining why the assassination was "a political necessity," and his religious book, The Truth.

At 9:30 a.m., Garfield entered the depot with Blaine, who was seeing him off.  Guiteau shot the president, grazing his arm and causing him to spin around; a second shot entered Garfield's lower back, four inches from his spinal column.  The police officer on duty, Patrick Kearney, had not seen the shooting, but apprehended Guiteau who was suspiciously running from the scene.  The president was soon transferred by ambulance to his White House bedroom, where Dr. D. W. Bliss and a team of physicians attended him. 

News of the shooting spread quickly, and the Washington Post printed an extra edition prematurely reporting the president's death.  In New York City, flags were lowered to half-mast, and then raised.  In the wake of Tsar Alexander's assassination by anarchists a few months earlier, some feared a conspiracy.  Upon his arrest, Guiteau proclaimed that he had avenged the Stalwarts and now Arthur would be president.  None of these men, of course, knew anything of Guiteau's plans.  Vice President Arthur was devastated by the news, refused to serve as acting president, and sobbed uncontrollably when the president finally died.  Senator Conkling paid a courtesy call to the sickbed of his political rival.

President Garfield had the best medical care that the nation could offer in 1881; in other words, it was terrible.  In the first two days, 15 physicians examined the president, many plunging their naked fingers into his wound to locate the bullet.  Finding the bullet, which was not accomplished until the autopsy, consumed an inordinate amount of time, even though people could lead normal lives with bullets in their bodies.  For the first weeks, Garfield was able to communicate and eat regularly (despite suffering from nausea).

On July 23, though, he began vomiting, running a high fever, and having chills.  On August 8, they operated on what they thought was the bullet track, but which turned out to be a pus channel.  In late August, when the president could no longer ingest food, the doctors gave him rectal enemas of broth and minced or watered food.  The president lost 130 pounds, and pus began draining from his mouth, nose, and ears.  He remained mentally alert, though not surprisingly, he became depressed.

On September 7, at the president's insistence, he was taken by train to the New Jersey shore.  He died there on September 19, 1881, just days short of his 50th birthday.  In New York City, Chester Arthur was sworn in as the 21st president of the United States.  Garfield's body lay in state in the Capitol rotunda for two days, during which thousands of mourners viewed his remains.  On October 14, 1881, Charles Guiteau was indicted for the murder of President James Garfield, and his trial lasted from November 1881 through late January 1882.  Although Guiteau's attorney pleaded his client's insanity, the jury took less than an hour to find him guilty as charged.  He was publicly hanged on June 30, 1882.