Papillary renal cell carcinoma (RCC) represents 10% to 15% of adult renal neoplasms; however, the molecular genetic events that are associated with the development and progression of sporadic papillary RCC remain largely unclear. Papillary RCCs can be divided into two subtypes based on histologic, cytogenetic, and gene expression differences. Type 1 tumors ( approximately 60-70%) are generally low grade with favorable outcome, whereas type 2 tumors ( approximately 30-40%) are associated with increased cytogenetic complexity, high tumor grade, and poor prognosis. In this study, computational analysis of gene expression data derived from papillary RCC revealed that a transcriptional signature indicative of MYC pathway activation is present in high-grade type 2 papillary RCC. The MYC signature is associated with amplification of chromosome 8q and overexpression of MYC that maps to chromosome 8q24. The importance of MYC activation was confirmed by both pharmacologic and short interfering RNA-mediated inhibition of active Myc signaling in a cell line model of type 2 papillary RCC. These results provide both computational and genetic evidence that activation of Myc is associated with the aggressiveness of papillary type 2 RCC. Therefore, it will be useful to consider inhibition of components of the MYC signaling pathway as avenues for therapeutic intervention in high-grade papillary RCC.