Over the last several decades, many new drugs that target molecular pathways in carcinogenesis and the inflammatory immune system have been developed, resulting in substantial improvements in the treatment of many malignancies and inflammatory conditions. However, an increasingly widespread deployment of these new drugs has revealed an increased tendency for patients to develop skin malignancy in some instances and questions of possible association between their use and skin cancer. Specifically, increased skin cancer risk has been reported in association with BRAF inhibitors, sonic hedgehog-inhibiting agents, Janus kinase (JAK) inhibitors, and phosphodiesterase 5 (PDE-5) inhibitors. We review the literature on each drug class and its association with skin malignancy, as well as recommendations regarding drug use, surveillance, and treatment.