Nucleoside reverse transcriptase inhibitors suppress HIV replication by blocking reverse transcriptase, an RNA-dependent DNA polymerase. These drugs can also affect cellular and mitochondrial DNA polymerases. Mitochondrial DNA polymerase gamma is particularly sensitive to nucleoside reverse transcriptase inhibitors, and the majority of adverse effects caused by nucleoside reverse transcriptase inhibitors are most likely caused by mitochondrial dysfunction. This article reviews the recent clinical implications of nucleoside reverse transcriptase inhibitor-induced mitochondrial toxicity and discusses options for management.