The transcription factor Microphthalmia (Mi) is a helix-loop-helix protein which plays an essential role in the development and subsequent function of neural crest-derived melanocytes. Since its discovery as a mutant allele producing mice devoid of viable melanocytes, Mi has emerged as the gene whose mutation is responsible for the human pigmentation condition Waardenburg Syndrome IIa, as well as a variety of cellular defects involving retinal pigment epithelium, osteoclasts, and mast cells. As discussed here, Mi has recently been recognized to be targeted by several signaling pathways of importance to melanocytes, those activated by melanocyte stimulating hormone (MSH) and Steel factor. While these two pathways profoundly modulate Mi activity, they do so via strikingly different mechanisms. The differences and similarities of these responses highlight the likely roles of Mi in influencing both pigmentation and proliferation/survival. These effects are also of significance in human melanoma, a tumor for which Mi appears to be an extremely sensitive and specific marker.