A combination of approaches have been used to identify genes that influence the normal diversity seen in human pigmentation and somatic mutations that drive the formation and growth of pigmented lesions. These have included comparative genomics 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, and large-scale mutation screening of lesion tissue. Candidate pigmentation 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, high degree of freckling as well as increased incidence of melanoma. An intronic SNP in a regulatory region of the IRF4 gene in Europeans has been implicated in pigmentation phenotypes through altered transcriptional expression of TYR, and has also been correlated with nevus counts. 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. We are determining the genetic association of variant alleles with pigmentation phenotypes in a collection of adolescent twins and melanoma patients, and in parallel through characterisation of cultures of human primary melanocytes derived from donor skin tissue selected based on pigmentation genotype. We are also conducting a study in 600 volunteers from Queensland to determine genetic correlations with pigmentation, nevus phenotype and the dermoscopic nevus subtypes in these individuals. We have found 10 patients in our cohort who carry the SUMOylation deficient MITF E318K mutation that has been described as a medium-penetrance melanoma gene.