Renal cell carcinoma (RCC) is the most common kidney cancer and includes several molecular and histological subtypes with different clinical characteristics. While survival rates are high if RCC is diagnosed when still confined to the kidney and treated definitively, there are no specific diagnostic screening tests available and symptoms are rare in early stages of the disease. Management of advanced RCC has changed significantly with the advent of targeted therapies, yet survival is usually increased by months due to acquired resistance to these therapies. DNA methylation, the covalent addition of a methyl group to a cytosine, is essential for normal development and transcriptional regulation, but becomes altered commonly in cancer. These alterations result in broad transcriptional changes, including in tumor suppressor genes. Because DNA methylation is one of the earliest molecular changes in cancer and is both widespread and stable, its role in cancer biology, including renal cell carcinoma, has been extensively studied. In this review we examine the role of DNA methylation in renal cell carcinoma disease etiology and progression, the preclinical use of DNA methylation alterations as diagnostic, prognostic and predictive biomarkers, and the potential for DNA methylation-directed therapies.