After working for the Peace Corps and as an aide to Congressman F. Bradford Morse, Tsongas successively won election as a city councilor and county commissioner.

In 1967, Tsongas – working as an aide to Congressman F. Bradford Morse – met Niki Sauvage, who was spending the summer in Arlington, Virginia.

However, in the massive Democratic wave of the post-Watergate election of 1974, he defeated freshman Republican Paul W. Cronin by a 21-point margin.

Increasingly popular and well-liked in Massachusetts, in 1978 he ran for and was elected to the United States Senate, defeating incumbent Republican Edward Brooke by 202,699 votes.

After undergoing a bone marrow transplant to treat the disease in 1986 and receiving a clean bill of health from doctors in 1991,[6] he returned to politics, running for his party's nomination for President in 1992.

In October 1979, after the Senate Energy and Natural Resources Committee voted in favor of Alaska public lands legislation, President Jimmy Carter issued a statement thanking Tsongas for his leadership in strengthening the bill.

[citation needed] Relative to business and economic matters, Tsongas focused in particular on the federal budget deficit, a cause he continued to champion even after his presidential primary campaign ended, by co-founding the Concord Coalition.

The Boston Herald editorialized that his political philosophy had "far more in common" with 1990s-era Republican Mitt Romney (who crossed over to vote for Tsongas in the 1992 primaries) than with traditional Massachusetts Democrats like Ted Kennedy.

"[15] Described as a "long shot campaign" by the New York Times, Paul Tsongas was the first Democrat to launch a bid for the 1992 presidential election, on April 30, 1991 in his hometown of Lowell, Massachusetts.

He achieved recognition for the bluntness and clarity of his plan, distributing a short book titled A Call to Economic Arms,[17] which focused on such issues as the growing federal deficit.

"[18] During the early weeks of 1992 things seemed to be going Tsongas's way when one major candidate, Bill Clinton, stumbled over issues involving marital infidelity and avoidance of the military draft during the Vietnam War.

But Clinton's setback proved temporary, bottoming out weeks before the New Hampshire primary so that while Tsongas won the most votes, and was declared the winner, the margin of 33.2% to 24.78% gave each candidate 9 delegates.

[citation needed] Clinton adviser James Carville then tagged his man "the Comeback Kid" and declared his campaign back on track, leaving Tsongas, still ostensibly the front-runner, to be seen by many as the underdog heading into Super Tuesday.

Tsongas won the primaries in Delaware, Maryland, Arizona, Washington, Utah and Massachusetts, but his campaign never recovered from Clinton's comeback.

Mr. Tsongas made his survival from cancer an issue in his Presidential campaign when he and two of his doctors, Dr. Tak Takvorian and Dr. George P. Canellos, said he had been cancer-free since a bone-marrow transplant in 1986.

In May 1996, he underwent another transplant, getting bone marrow from his twin sister, Thaleia Schlesinger, to correct myelodysplasia, a bone-marrow disorder that can occur in people who have recovered from lymph cancer.On January 27, 1998, the Tsongas Center in Lowell was dedicated in his honor.