Once abandoned because of devastating teratogenic effects, thalidomide has reemerged as an alternative treatment in many dermatologic diseases. In 1998, thalidomide became FDA approved for the acute treatment and suppression of the cutaneous manifestations of erythema nodosum leprosum (ENL). ENL is a systemic disorder that typically occurs after several years of antileprosy treatments, usually for lepromatous leprosy. Off-label uses for thalidomide include: aphthous stomatitis, Behçet disease, pyoderma gangrenosum, chronic discoid lupus erythematosus, systemic lupus erythematosus, lichen planus, prurigo nodularis and sarcoidosis. This review examines the background, pharmacokinetics, mechanism of action, side-effects, and indications of thalidomide.