The Microphthalmia-associated transcription factor (Mitf) is required for the proper development of several cell lineages including osteoclasts, melanocytes, retinal pigment epithelial cells, mast cells and natural killer cells. Mutations in Mitf in multiple organisms result in osteopetrosis due to defective osteoclast development. Mitf is a member of the basic/helix-loop-helix/leucine zipper (b-HLH-ZIP) transcription factor subfamily named MiT, which also includes Tfe3. Genetic evidence indicates that Mitf and Tfe3 carry out essential functions in osteoclast development. Mitf has been shown to reside downstream of the macrophage colony-stimulating factor (M-CSF) and receptor activator of NF-kappaB ligand (RANKL) signaling pathways that are critical for osteoclast proliferation, differentiation and function. Mitf and Tfe3 have been shown to regulate the expression of several target genes necessary for bone degradation by mature osteoclasts. Here, we review the bone and osteoclast phenotypes of animals with mutations in Mitf and Tfe3, Mitf's interaction partners and signaling pathways, and known target genes which, together with others yet to be identified, likely represent key effectors of bone resorption.