The distinction between chromophobe renal cell carcinoma, the granular cell variant of clear cell renal cell carcinoma, and renal oncocytoma is a common diagnostic dilemma. The usefulness of KIT, CD10, RCC, and RON in the differential diagnosis of these renal epithelial tumors was investigated. KIT was 100% positive in chromophobe renal cell carcinoma (11 of 11) and renal oncocytoma (12 of 12). The KIT staining pattern was identical in both tumor types, with cytoplasmic membrane attenuation, and fine granular cytoplasmic staining. In contrast, KIT was absent in all granular cell variants of clear cell renal cell carcinoma (0 of 6). RCC was observed in more than 80% of the granular cell variant of clear cell renal cell carcinoma (5 of 6) but was negative in all chromophobe renal cell carcinomas (0 of 11) and renal oncocytomas (0 of 12). CD10 was expressed in 100% of the granular cell variant of clear cell renal cell carcinoma (6 of 6), 72% of chromophobe renal cell carcinomas (8 of 11), and 58% of renal oncocytomas (7 of 12). RON was 100% positive in the chromophobe renal cell carcinomas (11 of 11) and renal oncocytomas (12 of 12) but only 50% positive in the granular cell variant of clear cell renal cell carcinoma (3 of 6). Colloidal iron was diffusely and strongly positive in more than 80% of the chromophobe renal cell carcinomas (9 of 11), focally and weakly positive in 41% of the renal oncocytomas (5 of 12) but negative in all granular cell variant of clear cell renal cell carcinoma (0 of 6). The above results demonstrate that: 1) KIT is a very sensitive marker for both chromophobe renal cell carcinoma and renal oncocytoma; 2) immunohistochemistry using antibodies to KIT combined with RCC was sufficient to discriminate between chromophobe renal cell carcinoma and the granular cell variant of clear cell renal cell carcinoma; and 3) neither RON, nor KIT, nor a combination of this panel can be used to distinguish chromophobe renal cell carcinoma from renal oncocytoma. Colloidal iron staining aided in this distinction for the majority of the chromophobe renal cell carcinomas (more than 80% positive) and renal oncocytomas (close to 60% negative).