Thalidomide has reemerged as a potential drug with new found uses despite its history of having caused devastating congenital birth defects. The drug has become the subject of major interest because of its clinical value in certain clearly defined disorders. Interest in thalidomide was initially rekindled in the mid-1960s by its remarkable effect in lessening the complication of leprosy called erythema nodosum leprosum. Several studies thereafter have demonstrated the use of thalidomide as a wonder drug. However, it was only in July 1998 that the US Food and Drug Administration granted approval for the use of thalidomide under strict patient guidelines. Its apparent immunomodulatory and anti-inflammatory properties led to widespread application in clinical practice. Thalidomide has gained respectability as a promising new drug in oral mucosal lesions. Studies have suggested that thalidomide is effective in severe aphthous stomatitis, Behçet’s syndrome, certain oral manifestations of human immunodeficiency virus (HIV) infection, erosive lichen planus, and possibly malignancies.