Clear cell renal cell carcinoma (ccRCC) is the most common form of neoplasm occurring in the adult kidney. Although significant advances have been made in treatment for ccRCC, a significant percent of patients have no benefit from currently available treatment option. MicroRNAs (miRNAs) have been reported to play central roles in regulating tumor progression, and are being explored as potentially more effective therapies and diagnostic tools for various cancers. The transcription factor E26 transformation specific-1 (ETS1) is believed to be intimately involved in tumor progression, and is frequently upregulated in tumors, including ccRCC. However, few studies have investigated the implications of ETS1 in ccRCC, and no studies have investigated the dysregulated mechanisms responsible for aberrant ETS1 expression in ccRCC. We used databases, clinical samples and target prediction algorithms to investigate aberrant miR-377 expression and potential targets in ccRCC. Our results indicate that miR-377 is downregulated in ccRCC, and that miR-377 can regulate the expression of ETS1. Further, using cell cycle analysis, MTT, luciferase and knockdown experiments, we found evidence to suggest that ETS1 is central in the development of the proliferative, metastatic and invasive phenotype of ccRCC cells. Furthermore, miR-377 was found to directly downregulate the expression of ETS1 and reduce the ability of ccRCC cells to proliferate, migrate and invade. As miR-377 was found to be differentially expressed in ccRCC, and in light of the apparent central role of ETS1 in tumor development, our results indicate that miR-377 could be useful for ccRCC diagnostics, prognostics and therapeutics.