He was counsel to the State of Minnesota and Blue Cross and Blue Shield of Minnesota against the American tobacco industry, suing in 1994 as the second of eventually 46 states to join in the tobacco litigation. Ciresi's Minneapolis law firm, Robins, Kaplan, Miller & Ciresi, of which he is the chairman, settled with the tobacco companies in 1998 with an agreement for the tobacco defendants to pay the state of Minnesota $6 billion. The law firm donated $30 million to the Minneapolis Foundation in 1998, a contribution made possible by the settlement fee; at the time, the gift was thought to be the largest contribution from a law firm to a community foundation. Mike serves on the Board of Trustees of his alma mater, the University of St. Thomas, as the Board of Governors of the University of St. Thomas School of Law. He currently serves on the board of Regions Hospital Foundation and Minnesota Early Learning Foundation.
Ciresi's law firm was frequently mentioned in the press for the remarkably high legal fees collected in the 1998 tobacco settlement, fees variously reported as between $440 million and $558 million. The fees were to be paid over two years, in contrast to the 25-year annual payment scheme used to pay the plaintiffs of the case, the State of Minnesota. Hence, the time-adjusted value (or net present value) of the Ciresi firm's fees, relative to the total award, was enhanced. The fees were funded directly by tobacco companies.
"Marlboro has risen to its No. 1 position on the backs of America's youth," Ciresi said in January 1998.
As a result of the 1998 Minnesota tobacco settlement, Ciresi came to be known as a wealthy man and philanthropist, appearing regularly in the national and local press. According to Forbes magazine, with Ciresi among the highest-paid lawyers in the USA, "Cigarette money alone put these ten lawyers on the top-earning list—and it's likely to keep them there for the next 25 years." The magazine listed Ciresi's personal annual income at $14.4 million in 2000. Forbes speculated that Ciresi would use his newfound wealth and prominence to run for political office, which soon proved correct.
Ciresi served as counsel to the Government of India against Union Carbide over the Bhopal catastrophe. He was counsel to women rendered infertile by the Copper 7 IUD and to the families of women killed by the Dalkon Shield IUD.
Ciresi ran in the 2000 Senate primary for the Democratic-Farmer-Labor Party (DFL), spending several million dollars of his own money on the campaign. Ciresi ran as a self-described progressive moderate, and was endorsed by the Sierra Club and the Minnesota Nurses' Association. Ciresi was handily defeated by Mark Dayton, an heir to the founders of Target Corporation, in the four-way DFL primary. Dayton then came from behind in the polls to defeat first-term incumbent Republican Senator Rod Grams in the general election.
Dayton announced in early 2005 that he would not seek a second term in the 2006 elections. Although Ciresi indicated an interest in the race and registered the domain name ciresiforsenate.com within 48 hours of Dayton's announcement, he announced on February 7 that he would not seek the nomination. He would have faced Hennepin County district attorney Amy Klobuchar and Ford Bell in the DFL primary.
On April 18, 2007, Ciresi announced that he would seek the DFL endorsement for the Senate seat held by Norm Coleman. Other Democrats in the race included author and satirist Al Franken, professor and author Jack Nelson-Pallmeyer, and Human Rights Activist Jim Cohen. On March 10, 2008, Ciresi announced his withdrawal from the primary.
On June 7, 2008, the Minnesota DFL endorsed Franken. Ciresi was widely reported on June 11 as saying he was "leaving all options on the table" when questioned about a possible primary run against Franken . But Ciresi eventually dropped out of the race without challenging Franken in the primary.