Isotretinoin (13-cis-retinoic acid) is widely used for the treatment of severe acne as well as for disorders of conification, for psoriasis, and for skin cancer prevention. As a member of the retinoid family, it has a wide spectrum of side effects, including reproductive, cutaneous, ocular, neurological, musculoskeletal, and hepatic. As long as patients are able to tolerate these side effects, it can be a very effective treatment option. This article examines both the most common and the most concerning side effects as well as ways in which providers and patients may best manage them to be able to benefit from isotretinoin treatment.