Assuming we are talking non-primaries --
Kay Hagan defeating Elizabeth Dole in 2008 was a pretty big one. I never saw it coming and think very few did until the 11th hour.
Scott Brown upsetting Martha Coakley in the 2009 MA special election.
Former Washington Sen. Slade Gorton was involved in two big upsets. In the 1980 Reagan Revolution, then AG Gorton upset the legendary Sen. Warren Magnuson. Twenty years later, Gorton (at the height of his power in Congress) was upset by Maria Cantwell. At the time, I believe Cantwell's defeat of Gorton in 2000 was the closest (2,229 votes) in U.S. Senate history.
It was a landslide compared to this one.
http://en.wikipedia.org/wiki/United_States_Senate_election_in_New_Hampshire,_1974
