Renal cell carcinoma (RCC) is the most common neoplasm of the adult kidney. The role of the von-Hippel-Lindeau (VHL) tumour suppressor gene is well established in RCC with a loss of VHL protein leading to accumulated hypoxia-induced factor (HIF) and the subsequent transcriptional activation of multiple downstream targets. Recently, microRNAs (miRNAs) have been shown to be differentially expressed in RCC and their role in RCC pathogenesis is emerging. This month, in BMC Medicine, Gleadle and colleagues show that certain miRNAs are regulated by VHL in either a hypoxia-inducible factor (HIF)-dependent or HIF-independent manner in RCC. They also show that miRNA expression correlates with the survival of RCC patients.In this commentary, we discuss the current understanding of the role of miRNAs in RCC and the different possible scenarios of their involvement in RCC pathogenesis. We also address their clinical significance as tumour markers, together with the potential use of miRNAs as therapeutic targets. Finally, we discuss some of the challenges that face the fast-evolving field of miRNAs, including the identification and validation of miRNA targets and the difficulties associated with establishing a link between miRNA expression and biological effects. A more thorough understanding of the biological nature of miRNAs and careful experimental planning will help us to reveal the complex role that miRNAs play in RCC pathogenesis. See research article: http://www.biomedcentral.com/1741-7015/8/64.