Mutation of microphthalmia transcription factor (MITF) results in deafness, bone loss, small eyes, and poorly pigmented eyes and skin. The primary cell types affected in MITF-deficient mice are melanocytes, osteoclasts and mast cells. A search for MITF-associated proteins, using a mast cell library that was screened with a construct that encodes the basic helix–loop–helix leucine zipper (bHLH-Zip) domain of MITF, resulted in the isolation of the protein kinase C interacting (PKCI) protein 1 and protein inhibitor of activated STAT3 (PIAS3). We have accumulated clear evidence of a function for these two proteins as repressors of MITF-induced transcriptional activity. Here, we describe this evidence and ideas that give some insight into the cellular network of interactions between various transcription factors and MITF.