Add to those impending departures the death of Sen. Edward Kennedy in 2009 and the state's loss of a House seat in the most recent redistricting process, and some Democrats in Massachusetts are wondering whether the glory days are behind them.
While the state's senior senator, John Kerry, has a powerful perch as chairman of the Senate Foreign Relations Committee and often serves as a troubleshooter across the globe for the Obama administration, there's been plenty of speculation that if Obama wins re-election, Kerry could be tapped to succeed Secretary of State Hillary Rodham Clinton.
That would rob Massachusetts of a strong Senate presence.
Part of the decline is due to inexorable demographic changes that are working against the relatively small Northeastern state.
While Southern and Southwestern states have experienced population booms, Massachusetts has seen anemic growth, leading to the loss of one of its 10 seats in Congress.
The prospect of running in a newly redrawn district with 325,000 new constituents, combined with the Democrats' loss of control of the House, prompted Frank's decision not to run again after more than three decades in Congress, the 71-year-old said.
"One of the advantages to me of not running for office is that I don't even have to pretend to be nice to people I don't like," the famously acerbic Frank said.
There was a time not so long ago when Massachusetts Democrats held outsized political sway in Washington.