OBJECTIVE To review the pharmacology, pharmacokinetics, efficacy, and safety of apricitabine, a nucleoside reverse transcriptase inhibitor that is currently under investigation and has fast-track approval status with the Food and Drug Administration. METHODS A literature search was conducted using PubMed (1966-June 2009) to retrieve relevant material using the search terms apricitabine, SPD754, and AVX754. References from selected articles were evaluated to identify other pertinent trials. Information was also obtained from the manufacturer. METHODS All English-language in vitro and in vivo studies and abstracts evaluating apricitabine were reviewed and considered for inclusion. Preference was given to human data. RESULTS Apricitabine is a prodrug that is phosphorylated to its active triphosphate form intracellularly, which ultimately results in chain termination and inhibition of reverse transcription. Apricitabine is administered orally, displays linear pharmacokinetics, and is renally excreted with minimal to no hepatic metabolism. It has demonstrated antiretroviral activity against drug-resistant strains both in vitro and in vivo. In clinical studies, in both antiretroviral-naïve and treatment-experienced patients, apricitabine achieved the primary endpoint of significant reductions in plasma viral load versus comparator. Further Phase 2 and 3 studies are currently enrolling. Safety analysis indicates that apricitabine is well tolerated and has a low potential for causing mitochondrial damage. The most common adverse events reported include headache and rhinitis. Development of resistance or further gene mutations has not been shown in clinical studies to date. CONCLUSIONS Although the role of apricitabine in the treatment of HIV-1 infection has yet to be established, its activity against resistant HIV-1 strains and its tolerability profile will likely make it a viable second-line treatment option in patients who have failed regimens containing lamivudine or emtricitabine.