Clear cell renal cell carcinoma (ccRCC) is the major and aggressive subtype of RCC. Previously, we identified 383 differentially expressed genes by analyzing full-length cDNA libraries of ccRCC and normal kidney tissues. In this study, we applied functional network analysis to the differentially expressed genes for identifying deregulated molecular pathways in ccRCC, and the results indicated that MYC showed a prominent role in the highest scoring network. The upregulation of MYC expression was validated in ccRCC tissues and cell lines. Furthermore, Knockdown of MYC expression by MYC-specific siRNA significantly inhibited the abilities of uncontrolled proliferation, anchorage-independent growth and arrested cell cycle in the G0/G1 phase in ccRCC cells. Moreover, we found that 37 differentially expressed genes were shown to be MYC-target genes, and the upregulation of the MYC-target genes BCL2, CCND1, PCNA, PGK1, and VEGFA were demonstrated. The expression of these MYC-target genes was significantly correlated with the expression of MYC in ccRCC tissues, and knockdown of MYC also suppressed the expression of these MYC-target genes in ccRCC cells. The recruitment of MYC to the promoter regions of BCL2, CCND1, PCNA, PGK1, and VEGFA was shown by Chromatin immunoprecipitation assay. These results suggest that MYC pathway is activated and plays an essential role in the proliferation of ccRCC cells.