The congressman kept a low profile for years, avoiding interview requests and public appearances.
It wasn't until this year that glimpses of Jackson's former self emerged. He was forced to campaign seriously for the first time in years when former Rep. Debbie Halvorson put up an intense primary challenge. He easily won and gave a triumphant victory speech with his wife and children by his side.
Neither Jackson's family nor staff ever fully explained what was happening with the congressman's health or if he'd return at all. A few times, staff seemed optimistic and so did voters in his Chicago-area district where he easily won re-election to a ninth full term this month despite, despite his only communication with voters coming through a robocall in which he asked for patience.
The timing of Jackson's leave and the way it was handled invited more scrutiny. Jackson's leave was announced just after a former fundraiser connected to the Blagojevich allegations was arrested on unrelated medical fraud charges.
The resignation left the House committee's investigation in the air. Since Jackson is no longer a congressman, the panel no longer has the power to punish him but could release a final report detailing its findings. A committee spokesman did not immediately return a message on Wednesday.
Reaction to his resignation was swift.
Democratic Leader Nancy Pelosi said in a statement that she'd spoke with both Jesse Jackson Jr. and his father Wednesday afternoon and accepted the news with "great sadness."
Rep. Danny Davis, a fellow member of Congressional Black Caucus, said Jackson's senior position on the House Appropriations Committee and his leadership would be missed. But he also said the way in which Jackson was leaving tarnished his image.
"It certainly does not leave his legacy untouched in as positive light as one would have hoped and wanted," he said.
He declined to comment on the federal investigation, saying he had no details, but the issue did appear to resonate with some voters.
"It was time," said retiree Gloria Pryor, who has voted for Jackson several times. "If he's done the things he's accused of doing then he should leave and apologize to the people of this community."
The vacancy left by Jackson's departure creates a rare opportunity for someone else to represent his district, which is made up of South Side Chicago neighborhoods, several southern suburbs and some rural areas.
Even before the resignation the gambit of potential successors floated around Chicago. Prominent Chicago attorney Sam Adam Jr., a onetime attorney for Blagojevich and R&B singer R. Kelly, said he'd be interested. Other names circulating are Chicago Aldermen Sandi Jackson and Anthony Beale, Cook County Board President Toni Preckwinkle and Halvorson.
Illinois Gov. Pat Quinn, a Democrat, has five days to schedule an election to replace Jackson, and the election must be held within 115 days, according to election officials. Quinn said he planned to schedule both a primary and a general election.
Henry C. Jackson reported from Washington. Associated Press Special Correspondent David Espo in Washington and Associated Press writer Sara Burnett in Chicago contributed to this report.