A distinctive subset of renal carcinomas is associated with Xp11. 2 translocations and resulting TFE3 gene fusions (PRCC-TFE3, PSF-TFE3, NONO-TFE3, ASPL-TFE3), encoding related aberrant transcription factors. We report the cloning of a novel clathrin heavy-chain gene (CLTC)-TFE3 gene fusion resulting from a t(X;17)(p11.2;q23) in a renal carcinoma arising in a 14-year-old boy. The fusion transcript joined the 5' exons of CLTC on chromosome band 17q23 to the 3' exons of TFE3. CLTC encodes a major subunit of clathrin, a multimeric protein on cytoplasmic organelles, and is a known recurrent fusion partner of the ALK tyrosine kinase gene in anaplastic large-cell lymphoma and inflammatory myofibroblastic tumors. The predicted CLTC-TFE3 product retains the nuclear localization and DNA-binding domains of TFE3, but lacks the multimerization domain of CLTC. The present renal tumor demonstrated morphologic and immunohistochemical features of both PRCC-TFE3 and ASPL-TFE3 carcinomas, including strong nuclear immunoreactivity for the TFE3 C-terminal and only minimal expression of epithelial proteins. However, unlike most renal carcinomas, it also focally expressed melanocytic proteins. The present report highlights the promiscuity of certain genes involved in chromosomal translocations. Further analysis of the shared features of CLTC and other TFE3 fusion partners may shed light on the essential biology of TFE3 fusion proteins.