Abstract: Targeted therapeutic strategy for cancer stem cells (CSCs) is the key to prevent tumor relapse and metastasis. The important roles of epigenetic regulation on the development of stem cells and gene reprogram of somatic cells suggest that this process may remarkably affect the occurrence and development of CSCs. The epigenome, which comprises DNA methylation, histone modifications, chromatin structures, and non-coding RNAs, controls gene expression patterns. In renal cell carcinoma (RCC), aberrant changes occur in the epigenome. To date, cells with CSC properties from RCC have been successfully isolated using different methods, such as sorting using the Hoechst 33342 side population, forming tumor spheroid, and sorting CD105 cell surface biomarker. According to the progress in genetic studies on RCC, in addition to DNA sequence, the abnormality in the regulatory mechanism has considerable functions in tumor progression. Epigenetic changes may be integral to the behavior of cancer progenitor cells and their progeny. Knowledge on epigenetics in renal tumorigenesis process is beneficial in the development of new therapeutic modalities and may deliver new prognostic and early diagnostic markers. This paper reviews the latest development in the study of RCC stem cells and the underlying mechanisms of epigenetic regulation on the development of CSCs in RCC.