Thalidomide (TD) is the drug in clinical use since over half a century for variable indications such as Leprosy. In 1960s, the use of TD lead to birth of about 10,000 babies with phocomelia. Later on, TD was removed from the market. In spite of Thalidomide Embryopathy (TE), this drug has recently been approved for the treatment of multiple myeloma for specific indications. Species resistance to develop limb deformities was the main reason of its unrecognized teratogenicity during preclinical toxicity testing. The purpose of this review is to discuss the brief history of this drug and the current discovery of a possible mechanism of species- specificity of TE involving SALL4 degradation by Thalidomide-Cereblon (TD-CRBN) complex.