This paper examines the existing literature and MedWatch reports concerning a proposed relationship between isotretinoin and depression and suicide. The authors provide a brief overview of the biology of isotretinoin and depressive disorder and find no basis for a putative molecular mechanism linking the two. They also address the complexities of Substance-Induced Mood Disorder (SIMD) as a psychiatric diagnosis and its relevance to isotretinoin. Based on this review, the authors conclude that there is no evidence to support a causal connection between isotretinoin and major depression or suicide, because reported cases do not meet the established criteria for causality. The authors also conclude, however, that it is important for dermatologists to be aware of the risk factors for suicide and to monitor patients who exhibit depressive symptoms.