The title came from a 1944 Roy Acuff song of the same name.
The lyrics are about a man who confronts his mortality when he discovers a car accident on a country road. Springsteen explained in his book Songs: "On a rainy highway the character witnesses a fatal accident. He drives home, and lying awake that night next to his lover, he realizes you have a limited number of opportunities to love someone, to do your work, to be a part of something, to parent your children, to do something good."
This is the last song on The River, a double album containing a mix of emotional ballads and uptempo rockers.