Thalidomide was a widely used drug in the late 1950s and early 1960s for the treatment of nausea in pregnant women. It became apparent in the 1960s that thalidomide treatment resulted in severe birth defects in thousands of children. Though the use of thalidomide was banned in most countries at that time, thalidomide proved to be a useful treatment for leprosy and later, multiple myeloma. In rural areas of the world that lack extensive medical surveillance initiatives, thalidomide treatment of pregnant women with leprosy has continued to cause malformations. Research on thalidomide mechanisms of action is leading to a better understanding of molecular targets. With an improved understanding of these molecular targets, safer drugs may be designed. The thalidomide tragedy marked a turning point in toxicity testing, as it prompted United States and international regulatory agencies to develop systematic toxicity testing protocols; the use of thalidomide as a tool in developmental biology led to important discoveries in the biochemical pathways of limb development. In celebration of the Society of Toxicology’s 50th Anniversary, which coincides with the 50th anniversary of the withdrawal of thalidomide from the market, it is appropriate to revisit the lessons learned from the thalidomide tragedy of the 1960s.