SummaryThe hand-foot-syndrome (HFS, palmoplantar erythrodysesthesia, chemotherapyassociated acral erythema) is characterized by painful predominantly palmoplantar lesions. The association with different chemotherapeutic agents has been known for over 20 years. More recently, HFS has been reported in association with regimens using targeted agents, in particular the multikinase inhibitors (MKI) sorafenib and sunitinib. The HFS associated with MKI has a different distribution and clinical appearance than the traditional disorder. In this review, similarities and differences between chemotherapy-and MKI-associated HFS are discussed and current recommendations for their prophylaxis and management are summarized.