Much of the resistance of melanoma to immunotherapy,radiotherapy and cytotoxic treatment is due to an impressivearray of molecular defences that derive ultimately from theessential molecular structure of the melanocyte and its biolo-gical requirement for defence against apoptosis. The explora-tion of melanoma susceptibility genes like CDKN2A (inheritedin mutated form in 30–40% of families with multiple melan-oma-affected members), CDK4 and MC1R has highlighted anumber of key pathways in melanomagenesis. Others havebeen revealed by a systematic exploration of somatic chro-mosomal and genetic abnormalities in naevi and melanomas.Constitutive activating mutations in Nras and BRAF are themost common somatic oncogene mutation in melanoma,indicating the importance of this pathway in the deregulationof melanocyte growth. Downstream targets of this signallingpathway include the cell cycle regulator cyclin D1 and themelanocyte-speciﬁc transcription factor, MITF. BRAF muta-tions are also seen in 60–80% of benign melanocytic naevi.This suggests that the complex molecular machinery of checksand balances in the cell normally protects against the unre-strained growth stimuli propagated through such abnormalit-ies in the Ras/RAF signalling pathway. The CDKN2Aproduct, p16INK4A is induced by activation of the BRAFpathway and under normal circumstances induces cellularsenescence. Escape from this senescence is probably funda-mental to melanomagenesis. Melanoma-associated NRas andBRAF mutations do not carry the UV-induced ﬁngerprint,and BRAF mutations appear to be more common in melan-omas arising in non-chronically sun-damaged skin and in thosewith multiple naevi. They are rare in mucosal melanomas andin cutaneous melanoma arising in chronic sun-damaged skin(Curtin, JA et al. N Engl J Med, 353: 2005). The alternateprotein product of the CDKN2A gene, p14ARF binds hdm2leading to stabilisation of the central apoptosis regulator, p53.Inhibitors of apoptosis, like Bcl-2 and Mcl-1 are frequentlyover-expressed in established melanomas, accounting in partfor the observed resistance of melanoma to cytotoxic attack.