The centra theme of Hirst's work has been an exploration of mortality, a traditional subject that Hirst has updated and extended with wit, verve, originality and force. He is best known for a series of works (The Natural History series) in which dead animals are presented as memento mori in forms ironically appropriated from the museum of natural history rather than of art. Their titles suggest a range of readings and reveal the thoughtfulness of his approach. The artwork itself has a visual power that is virtually unmatched by any possible description of it. One cannot really hope to understand it, or even visualise it without experiencing it firsthand. This, many people believe, is the reason Damien was short listed for the Turner Prize in 1992. Even his own supporters do not always acclaim his work. The popularity of Hirst's unique brand of artistic statement tends to cycle in phases of favour and disdain. Damien blames this occasional lack of success not on the public, but on the press. He says that the media convinces the public to believe the art critics' erroneous assumptions about art, so the public accepts these opinions without ever actually viewing the art.

Even so, Damien constantly has to explain his work. Besides the controversial animal exhibits, there are sculptures, spot paintings and spin paintings. Damien now insists that when the spin paintings are displayed, they are equipped with a mechanism that makes them revolve on the wall because he was tired of people asking which way was up. The spot paintings have become somewhat of an icon of Damien's work. Another consistent theme in Damien's work is medical paraphernalia, (with which he has been obsessed for many years). The inspiration for his pharmacy pieces was the desire to make art that people really believe in, like they do medicine. "Pharmacies provoke an idea of confidence, of trust in minimalism. I love medical logos, so minimal, so clean, there's something dumb about it". His pieces like Substitute, Holidays/No Feelings and God are meant to parody the Western notion that medicine and chemicals can help a person to cheat death. "You can only cure people for so long and then they're going to die anyway... You can't arrest decay, but these works suggest you can".