This isn't the first time religion has been 'an issue' in the USA, but, last the time the issue actually surrounded an election.

Then Seantor John F. Kennedy was a Catholic and the opposition to his candidacy believed the Pope would run the country and not the President. 

It can be said, under George W. Bush, the Pope did.

...While the so-called religious issue is necessarily (click title to entry - thank you) and properly the chief topic here tonight, I want to emphasize from the outset that I believe that we have far more critical issues in the 1960 campaign; the spread of Communist influence, until it now festers only 90 miles from the coast of Florida -- the humiliating treatment of our President and Vice President by those who no longer respect our power -- the hungry children I saw in West Virginia, the old people who cannot pay their doctors bills, the families forced to give up their farms -- an America with too many slums, with too few schools, and too late to the moon and outer space. These are the real issues which should decide this campaign. And they are not religious issues -- for war and hunger and ignorance and despair know no religious barrier.
But because I am a Catholic, and no Catholic has ever been elected President, the real issues in this campaign have been obscured -- perhaps deliberately, in some quarters less responsible than this. So it is apparently necessary for me to state once again -- not what kind of church I believe in, for that should be important only to me -- but what kind of America I believe in....