Tenofovir disoproxil fumarate is approved to treat HIV infection in combination with other antiretroviral agents. Although tenofovir is generally well tolerated, the potential for nephrotoxicity exists based on preclinical data, case reports, and observational studies. Following its approval in the United States in October 2001, a series of case reports of tenofovir-related renal toxicity brought the issue to the attention of clinicians. While case reports raise the issue of nephrotoxicity, cohort studies and clinical trials have helped to clarify the overall safety profile of tenofovir. We present a review of the renal safety of tenofovir and provide a brief summary of the clinical implications of these data.