Palmar plantar erythrodyesthesia or hand–foot skin reactions (HFSR) are commonly associated with multikinase inhibitors targeting VEGFR and other angiogenic targets, and are thought to represent a Koebner phenomenon. This refers to provocation of skin lesions by various triggers, mainly trauma, but also includes other causes of epidermal injury or inflammation such as exposure to extreme temperature (either freezing or burns), repetitive motion (friction or pressure forces) or other exposures, such as radiation or ultraviolet light.[ 33 ] Figure 5 is a representative example of HFSR associated with a multikinase inhibitor. The clinical presenting features of focal blister and callus-like formation in the palms and soles exposed to mechanical trauma with the targeted agents are distinct from the diffuse erythema with exfoliative desquamation and erosive lesions which can affect intertriginous skin seen in the HFSR associated with cytotoxic agents such as anthracyclines and pyrimidine analogues.[ 34 ] Shared histological findings on skin biopsy for both include keratinocyte necrosis, dilated blood vessels in the dermis with perivascular lymphohistiocytic infiltrates, parakeratosis, and epidermal acanthosis.[ 34-36 ] Chemotherapy-induced HFSR is thought to arise in part due to local toxicity of the concentrated excretion of the chemotherapy agents from eccrine sweat glands.[ 37, 38 ] This is not consistently demonstrated with HFSR associated with VEGFR TKIs.[ 39, 40 ] Nonetheless, the HFSR associated with either cytotoxic chemotherapy or the VEGFR TKIs is known to be worsened by combination therapy with bevacizumab.[ 41-43 ] Interestingly, however, HFSR is not typically seen with bevacizumab monotherapy, suggesting that although the VEGF pathway is contributory, isolated VEGF inhibition alone is insufficient to cause HFSR. This hypothesis is supported by the fact that the incidence of HFSR is higher with multikinase inhibitors compared to bevacizumab.