Rush is the only politician to have ever beat Barack Obama in an election in the 2000 Democratic primary for Illinois's 1st congressional district. Rush still represents that district and has since 1993.
His decision to retire at this point marks two dozen Democrats who are leaving the House, causing panic in the caucus as House Speaker Nancy Pelosi tries to cling to her party's majority in the lower chamber.
Pelosi can only afford to lose three seats to maintain a majority with a 221-213 split.
The Senate is even more precarious as it remains split at 50-50, with Vice President Kamala Harris making the tie-breaking vote in any party line results.
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The razor-thin margins have fueled Democrats' apprehensions that the GOP could take back a majority in either chamber and blockade Biden's agenda for the remainder of his first term.
A civil rights activist and ordained minister, Rush co-founded the Illinois chapter of the Black Panther Party in the 1960s and notes he intends to remain active in his ministry in retirement from Congress.
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Rush told the Chicago Sun-Times on Monday evening that he decided to retire following a conversation with his grandson, Jonathan, who says he wishes to learn more about his grandfather's history.
"I don't want my grandchildren to know me from a television news clip or something they read in a newspaper," Rush told the paper. "I want them to know me on an intimate level, know something about me, and I want to know something about them. I don't want to be a historical figure to my grandchildren."
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Last month, Rush disclosed that he had contracted Coronavirus but was asymptomatic as cases spiked at the Capitol in the midst of the nationwide Omicron surge.
Among veteran House Democrats stepping down include Representative Cheri Bustos, who said in April 2021 that she will not run for reelection this year.
Pelosi, 81, has signaled she will run for an 18th term and hasn't ruled out holding onto her leadership position.
So far, 11 House Republicans have also said they will not seek reelection.
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The party not in power historically has an advantage over the in-party in midterm elections, and as the President's poll numbers fall amid a worsening pandemic and fast-rising inflation, Republicans could seize an even greater advantage.