I nearly let the day slip away without recognizing the 15th anniversary of the greatest upset in the history of (regular-season) college football:
Northwestern 17, Notre Dame 15 (South Bend, 9/2/95)
This is one of those can-not-argue-about-this situations, although I'm happy to trot out plenty of supporting evidence.
For those under the age of 25, Notre Dame wasn't always mediocre; from the middle of the last century until its final years, Notre Dame DEFINED successful college football.
Similarly, from roughly the early 1970s through the mid-90s, Northwestern DEFINED losing college football.
Notre Dame was opening the season with championship aspirations (as always), playing at home, a 27.5-point favorite over an NU team with few aspirations beyond an unprecedented run for bowl eligibility.
But it is the symbolism -- NOTRE DAME(!) losing to NORTHWESTERN(!) -- that puts this at the top of the list of all-time great college football regular-season upsets.