The show primarily focused on the day's biggest sports topics and the humorous banter between the Mikes.

[1] Outside of a few radio stations that are able to move or decline carriage of the show for their own local morning productions (or for daytime-only operations, may not be able to carry), Mike & Mike was effectively a compulsory element of the ESPN Radio schedule, which all affiliates of the network were required to carry.

Mike Greenberg was portrayed as a stereotypical nerd and with a man-crush on whoever the starting quarterback was for his favorite team (the New York Jets), for whom he is openly partisan.

Regular guest hosts included Adnan Virk, Ric Bucher, Marcellus Wiley, Mike Golic Jr., and regular contributors Buster Olney, Mark Schlereth, Cris Carter, Herman Edwards and Trey Wingo.

When the TV simulcast began broadcasting in HD, the radio SportsCenter updates were no longer simulcast on ESPN2, replaced by TV-specific SportsCenter updates, usually anchored by Sage Steele, Jonathan Coachman, Darren Lyn, George Smith or Michael Kim.

It was announced in June 2007 that Greenberg and Golic would also call a National Football League game together for ESPN, broadcasting the second game of ESPN's Week 1 Monday Night Football doubleheader along with former NFL coach and player Mike Ditka.

[13] In June 2008, ESPN announced that the "Three Mikes" will return to broadcast the second game of the opening 2008 Monday Night Football doubleheader.

The duo was roasted on January 11, 2008, in Atlantic City, New Jersey, at the House of Blues, with a portion of the proceeds to benefit the V Foundation.

Guests included Jeffrey Ross, Frank Caliendo (pre-recorded video only), Mike Ditka, Chad Johnson, Clinton Portis, Ed Reed, Charlie Weis, Eddie Griffin, Joe Klecko, Trey Wingo, Mark Schlereth, Dana Jacobson, and Wink Martindale.

The Roast made national news when it was reported that an apparently intoxicated Jacobson cursed the University of Notre Dame and Jesus Christ.

Ratings for the duo were extraordinarily high, especially for being on the "minor league" of the ESPN networks only offered in a few markets on anything other than digital cable or satellite packages.

This change pushed the morning show Cold Pizza (now titled ESPN First Take) back till 10 a.m.

The new set features an informal interview area with lounge chairs, and a telestrator screen.

In 2005, ESPN and Animax Entertainment began producing two- to three-minute cartoons of Greenberg and Golic, called Off Mikes.

[19] "Sheet of Integrity" is a phrase coined by Mike Greenberg[20] describing a single bracket entry created for wagering on the NCAA basketball tournament.

Greenberg held the belief that if a person wishes to enter multiple pools, they should do so using the same picks for each entry.