Having turned 70 in August, he would be the oldest U.S. president to get elected. And he faces at least one strong challenger within the party, Massachusetts Gov. Mitt Romney, and others in the seemingly ascendant Democratic Party, such as Sens. Hillary Clinton, D-N.Y., and Barack Obama, D-Ill.
Moreover, McCain has yet to resolve the problems he's had with the Republican Party's conservative base.
"He has a problem with pro-lifers on judges. He … became very hostile to the Second Amendment community and supportive of gun control. He has a problem with the economic conservatives because he's been bad on taxes for six years now," said longtime critic Grover Norquist, president of Americans for Tax Reform, which includes individuals and businesses opposed to higher taxes.
"Conservatives who care about the tax issue are very concerned that he opposed Bush's tax cuts," Norquist said.
McCain has tried to combat that with goodwill. He appeared at 346 events for Republican candidates this election cycle and was said to be the most requested speaker for GOP candidates.
"He's built a base across the country, and unlike [in] 2000, John McCain will run a 50-state strategy," McKinnon said.
While emphasizing more bipartisan issues such as campaign finance reform and a patients' bill of rights early in the Bush presidency, McCain has more recently strongly supported the war in Iraq.
He may very well be the only serious presidential contender calling for more troops to go to Iraq.
While he opposes a constitutional amendment to ban same-sex marriage, he supported such an effort in his state -- an effort that failed.
McCain has also attempted to reach out to conservative evangelical leaders, as he did with the Rev. Jerry Falwell earlier this year.
Appealing to those conservatives while keeping the independents so important to his party's 2008 hopes may pose a considerable challenge.
ABC News' Ed O'Keefe, Mark Halperin and Teddy Davis contributed to this report.