A wide subset of semaphorins and their receptors play a crucial role in melanoma pathobiology and response to therapy: some of them being able to promote melanoma angiogenesis and metastatization (Sema5A, Sema6A, Sema7A, Neuropilin1 and 2, PlexinD1), while other being involved in the inhibition of tumor development or progression (Sema3A, Sema3B, Sema3F, Sema4D, PlexinB1, PlexinC1). The gene discussed is SEMA4D; the disease is melanoma.