The potential for the induction of mania, increased cycle frequency, and other behavioral adverse events associated with antidepressant exposure in patients with bipolar disorder is becoming an increasingly important area of research study, as this diagnosis receives wider recognition in youth. While the majority of studies in the adult literature, and much clinical experience suggest that precipitation of mania and cycle acceleration are common phenomenon, the retrospective nature of many of the published studies, different criteria for subject inclusion, and the application of statistical methods that are vulnerable to computational artifact, continue to raise some questions, and leave a number of methodological issues unresolved. This brief review of the adult literature addresses some of these key issues with the aim of encouraging further research in this area of clinical psychopharmacology.