There's a great interview on npr.org all about this song. It's about his struggle with religion and what or what not to believe.

I like the earlier version, Waiting for the Sunset, a lot more.

The introduction to this song is amazing, I love the piano.

"Can you get me there, friend?
Without a soul to sell along the way
The devil rides with me again
He always says everything's okay"

He gave up on Jesus, he is now a friend of the devil.

"Maybe I'm losing sleep over nothing
Maybe I'll be just fine
He tears me away from all those little things
That seemed so important when I knew you "

Maybe he used to date a Christian? In any case, when he dated this girl, he didn't cavort around with the devil.

"And can you get me there, friend?
You know the devil only holds a lease
And he's so hard to kick, man
It's been twenty years since I've been clean "

I think he means the devil has a lease on his soul, and therefore the devil is living inside of him. And it's been twenty years since the devil has been out of him.

"Maybe I'm losing sleep over nothing
He tells me I'll be just fine
He's in my blood, he's thicker than love
He seems so important, and you keep fading"

As this girl moves further and further out of the picture, the devil becomes a more and more important part of his life.

And I think the end is just him calling her and being rude on the phone. Possibly.

I don't think he is talking about Christian girl he used to date that moved further and further out of the picture as Fionar2001 suggested, but actually God Himself that he is moving further and further away from. As he gets closer to the devil, he looses touch with God. The devil he could possibly be talking about may be abusive habits like alcoholism or drug addiction when he says
"You know the devil only holds a lease
And he's so hard to kick, man
It's been twenty years since I've been clean"
or maybe just other bad habits that he just can't seem to give up. And when he says
"Maybe I'm losing sleep over nothing"
he means that he is stuggling with this internal conflict of whether to embrace God or the devil's ways; however, at the same time he isn't completely sure God even exists and maybe he is just wasting energy thinking about it.

this song got me thru a time period when my friend became an asshole and i didnt know which way to go.

"he tears me away from all those little things that seemed so important when i knew you"

personally.. ill stick with the devil :)

I agree with AllAboutThoseWords, the song doesn't necessarily have to be about Jesus, the Devil, or Christianity itself.
The song seems to describe a relationship between two people that may or may not be couples. I guess Jesus is supposedly the other, whereas the Devil is the singer. It describes that the Devil wants to be with Jesus, to have things work, but he can't due to his nature, or his being an assh*le, or Jesus' refusal to accept the Devil. Thus, it's an argument that can't be fixed.

this is their best song, imo. im not at all religious.. so for me this is about human weakness. everyone has their addictions and weaknesses. your body feels cold and your going no where. i cant even begin to say how many times i feel like im going no where.

Actually, I don't really know if anyone has already put this into words, but I don't think this song talks about religion at all. Every single time I hear this song, I feel like he's talking about something that corrupted him, and it was really hard to let go, at the point of turning into an addiction.
I don't know, everyone is entitled to his own interpretation, but I trully think he's referring to some sort of drug, or someone who made him feel addicted to that person.
What a great song, what a great band.