San Francisco has experienced three NFC Championship Games and one agonizing Super Bowl defeat since he took over in 2011. The talent-laden roster is finally realizing the potential that had been obvious during the dark days under Mike Nolan and Mike Singletary.
Yet the 49ers have still yet to secure that coveted sixth Super Bowl title, and Harbaugh's men will need to overcome a number of significant obstacles if they are to accomplish that goal in 2014.
Indeed, San Francisco faces a difficult schedule and will have to deal with the threat posed by its rivals in an NFC West division that is widely considered to be the best in the NFL.
In addition, the Niners might be without one of the key players in last season's run to the NFC title game for at least some of the campaign.
In ascending order, here are the five most difficult challenges San Francisco will need to overcome to finally achieve its dream of bringing the Vince Lombardi Trophy back to the Bay Area.
Note: Statistics courtesy of Pro Football Reference.