Renal cell carcinomas (RCC) associated with Xp11.2 translocations (transcription factor E3 gene fusions) are rare tumors predominantly reported in children. Although only a small number of adult Xp11.2 translocation RCC cases have been described, this is likely due to the possibility of this tumor being unrecognized because of its histologic similarity to either clear cell or papillary subtypes based on hematoxylin and eosin staining. Herein, we describe the first successful case of systemic treatment of metastatic Xp11 RCC with sunitinib, a currently accepted standard of care in metastatic RCC, and attempt to elucidate potential mechanisms behind sunitinib activity in this histologic subtype.