An increasing number of antiretroviral agents are available for the treatment of HIV infection. Many clinicians and patients prefer once-daily therapy, and this, in addition to accumulating evidence of toxicity associated with thymidine analogues, means many individuals commence a non-thymidine analogue-based regimen. Stavudine (d4T) is no longer recommended for initial therapy, and zidovudine (AZT) may also be associated with lipoatrophy. Despite investigations into nucleoside-sparing options, triple agent therapy with two nucleoside analogues [nucleoside reverse transcriptase inhibitors (NRTIs)] and a ritonavir-boosted protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI) remains the mainstay. In this article, we review the advantages, and drawbacks, of different non-thymidine NRTI backbones.