Thalidomide was first introduced in the 1950s, and its widespread use led to thousands of birth defects through the 1960s; it was quickly withdrawn from the market. A fortuitous discovery identified during treatment of patients with erythema nodosum leprosum led to the recognition of the potent anti-inflammatory effects of thalidomide and a resurgence of interest in the drug. In the ensuing decades, thalidomide has been recognized as a potential treatment option in a number of dermatologic conditions. This article reviews the history, pharmacology, mechanisms of action, and off-label uses of thalidomide and serves as a guide for dermatologists to comfortably and safely institute and monitor thalidomide to patients with cutaneous disease.