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James Hetfield wrote this song about his mother who died from cancer. He was struggling with his mother's death and was looking for a way to cope with his loss and deal with the pain. It has come to mean much more to many people, who relate to the message of general internal pain and loss and the inability to make sense or cope with it.
The music video is based on a painting, and it recurrently shows scenes of the biblical character Adam committing his first (or original) sin. It also flashes to numerous pictures of Jesus dying. Because of the video, many people feel that it is a representation of redemption and the remorse one feels for having sinned. (thanks, Bob - St. George, UT, for above 2)
Metallica performed this with the San Francisco Orchestra in 1999. This version can be found on the S&M CD. (thanks, alastair - sydney, Australia)