A large number of genes involved in melanin biosynthesis and melanosome biogenesis influence the normal diversity seen in human pigmentation. A combination of approaches have been used in recent years to identify these genes, including comparative genomics of candidate genes and identification of regions of the human genome under positive selection, together with genome-wide and specific allele association studies of skin, hair and eye colour. Candidate genes include the enzymes encoded by tyrosinase, tyrosinase-related protein-1 and dopachrome tautomerase (TYR, TYRP1 and DCT), the P-protein (OCA2) and the melanocortin-1 receptor (MC1R). Variant alleles of the MC1R gene resulting from a range of amino acid substitutions have been associated with red hair, fair skin, a high degree of freckling as well as increased incidence of melanoma. A single SNP located in a regulatory region upstream of the OCA2 locus is a major determinant of blue-brown eye colour inheritance in Europeans. Other population genetic studies have revealed specific polymorphisms within the MATP (SLC45A2) and NCKX5 (SLC24A5) protein coding regions associated with the degree of skin pigmentation. Our approach to understanding human melanogenesis takes advantage of ongoing parallel studies. Firstly, by determining the genetic association of variant alleles with pigmentation phenotypes in a collection of adolescent twins and melanoma patients. Secondly, through characterisation of cultures of human primary melanocytes derived from donor skin tissue selected based on pigmentation genotype. Direct testing of a range of clonal melanocyte cultures characterised for causal SNPs within TYR, OCA2, MC1R, SLC45A2 and SLC24A5 have assessed their impact on melanin content and tyrosinase enzyme activity.