The microphthalamia-associated transcription factor (MITF) is an integral transcriptional regulator in melanocyte, the lineage from which melanoma cells originate. This basic-helix-loop-helix-leucine-zipper (bHLHzip) protein is critical for melanocyte cell-fate choice during commitment from pluripotent precursor cells in the neural crest. Its role in differentiation pathways has been highlighted by its potent transcriptional and lineage-specific regulation of the three major pigment enzymes: tyrosinase, Tyrp1, and Dct as well as other pigmentation factors. However, the cellular functions of MITF seem to be wider than differentiation and cell-fate pathways alone, since melanocytes and melanoma cells appear to require an expression of this factor. Here, we discuss the transcriptional networks in which MITF is thought to reside and describe signaling pathways in the cell which impinge on MITF. Accumulating evidence supports the notion that MITF is involved in survival pathways during normal development as well as during neoplastic growth of melanoma.