Cosmetic defects in acne may provoke a wide range of mental disorders (depressive, social-phobic, etc.). Isotretinoin is a very effective acne treatment; hence, it usually resolves the associated mental disorders. However, more available data show the possible association of taking isotretinoin and the onset of a depressive syndrome that includes frank depression and even suicidal ideation. The frequency of depressive disorders during isotretinoin treatment varies from 1% to 11% in different studies, and it is unclear whether this is a consequence of isotretinoin therapy. Since it crosses the blood-brain barrier, isotretinoin affects the expression of a broad spectrum of genes in the limbic structures, thus affecting the function of the dopaminergic, serotonergic, and noradrenergic neurons involved in the regulation of mood and emotion. It was suggested that isotretinoin in high concentrations inhibits hippocampal neurogenesis and induces apoptosis of hippocampal cells. However, some studies do not confirm this pathogenic role, and isotretinoin was even reported to have a therapeutic effect in acne-associated depression. In this review, we highlight epidemiological data, the underlying molecular pathogenesis, and the aspects of prevention concerning retinoid-induced depression in acne from the practical point of view of a dermatologist.