The discovery of the intricate intracellular signaling networks that regulate normal cellular proliferation and survival but can also drive the oncogenic process when aberrantly activated has led to the emergence of targeted agents in oncology. The introduction of such agents has resulted in improved survival and more tolerable treatments, reducing systemic toxicities such as myelosuppression. Nevertheless, it has become evident that these agents are associated with a wide spectrum of dermatologic toxicities that often manifest in cosmetically sensitive areas and may affect the majority of patients. Associated pain and pruritus can negatively impact quality of life, resulting in dose modification or treatment interruptions that interfere with potentially life-prolonging therapy. Extensive efforts throughout the past decade have concentrated on describing the clinicohistopathologic characteristics, elucidating the underlying mechanisms, and investigating potential management strategies. Currently, however, proposed treatment guidelines arise from expert opinions, anecdotal evidence, and few data from clinical trials. This article reviews the spectrum of dermatologic toxicities associated with a variety of targeted agents used alone or in combination with other modalities, delineating their clinical presentation, underlying mechanisms, and management options.