Chemotherapeutic and molecularly targeted agents are associated with a wide array of cutaneous toxicities. Despite the variety of toxicities, surprisingly little is understood regarding the pathogenesis underlying these reactions. This article reviews the most common cutaneous toxicities of cytotoxic chemotherapy and molecularly targeted systemic therapy, including extravasation of chemotherapy, with a discussion of the known and postulated underlying mechanisms of action. The need for developing a greater understanding of the basis of these reactions through more detailed study is evident.