Acne vulgaris, a condition that can affect people at any age, is the most common cause of referral to a dermatologist. Isotretinoin (ITT) is the most effective treatment available, but serious adverse effects, including a possible association with depression and suicide, limit its use. We review the current literature regarding the association of ITT with depression and suicide. Case reports and database studies show a clear association, and this association is biologically plausible. Although prospective studies have opposite results, limitations make them unsuitable to identify a subgroup of patients who may be at risk of developing depression or suicidal ideation with ITT. Overall, it seems some people might be at risk, particularly those with a personal or family history of mental disorder, but further studies are needed to identify those patients who would benefit from an early referral to a mental health professional when ITT is initiated. Currently, no conclusions can be drawn, and it seems appropriate to regularly screen all patients on ITT for depressive symptoms and suicidal ideation and promptly refer them to a mental health professional if any are found.