Changes in pigmentation are frequently encountered in primary and metastatic melanocytic lesions. Pigmentation is determined by the activity of tyrosinase (TYR), the rate-limiting enzyme in melanin synthesis. Tyrosinase activity can be modulated at the genetic and/or epigenetic level. In this commentary I suggest that pigmentation can serve as an indicator for genetic and metabolic changes as follows. In TYR-negative, amelanotic melanomas cells, downregulation of TYR and other melanocyte-specific gene expression is likely to be mediated by dominantly acting oncogenes with impact on the transcriptional activity of the melanocyte-specific transcription factor Mitf. Ras and c-myc, shown to be active and upregulated in subclasses of melanoma tumors, have the potential to induce these changes. TYR-positive highly pigmented melanoma tumors are likely to reside in aerobic, well-vascularized microenvironment. In contrast, hypo- or amelanotic TYR-positive lesions suffer from reduced TYR activity due to an acidified microenvironment. These lesions might have encountered anaerobic conditions, and have adapted to the reduced oxygen by enhanced glycolysis, leading to extracellular acidification and activation of V-ATPase.