Hand-foot syndrome (HFS), also called hand-foot skin reaction, palmar-plantar erythrodysesthesia, acral erythema, and Burgdorf reaction, is a dose-limiting cutaneous toxicity of many chemotherapeutic agents. Recently, the multiple tyrosine kinase inhibitor class of novel targeted therapies, including sorafenib and sunitinib, has emerged as an important cause of HFS, with 10–28% of patients treated with sunitinib and 10–62% of patients treated with sorafenib reporting HFS. This review examines the epidemiology, clinical features, histopathology, pathogenesis models, prognostic implications, and management of HFS, with particular attention to HFS induced by sorafenib and sunitinib. The high prevalence of HFS reported by patients treated with these medications underscores the need for greater understanding of the pathogenesis and management of this syndrome.