Cell senescence is a permanent arrest of cell division following excessive proliferation or cellular stresses. It has emerged as a major physiological mechanism for tumour suppression, and increasing evidence implicates it in normal and abnormal aspects of ageing. The commonest known gene for familial melanoma is CDKN2A, encoding p16, a key mediator of senescence; and benign moles (naevi) appear to be senescent melanocyte clones following oncogene activation. Senescence has even been suggested to explain aspects of vitiligo. Clinical aspects of cell senescence will be reviewed. Data will then be discussed from our microarray analysis of gene expression changes in human melanocytes cultured to reach replicative senescence, including melanocytes deficient in p16. Unsurprisingly, a prominent theme is the downregulation of cell cycle-related genes, less pronounced in p16-deficient cells. We also see a signature previously reported in other senescent cells, known as the SASP, or senescence-associated secretory phenotype. Here, a range of secreted cytokines, proteases and angiogenic factors become expressed, mimicking processes seen in inflammation. Signatures of interferon and TGFβ signalling are found, with some differences between melanocyte strains. Perhaps less predictably, the senescent cells also show signatures of neural differentiation, especially in p16-deficient strains. Possible clinical implications and parallels of the findings will be discussed.