Several dual nucleoside reverse transcriptase inhibitor (NRTI) combinations provide efficacy when combined with a 3rd agent. However, there are a number of issues with current NRTI and nucleotide reverse transcriptase inhibitor (NtRTI) combinations that often lead to treatment failure and limited treatment options. These issues include suboptimal potency, drug interactions, toxicities, tolerability issues, and selection of resistance mutations that confer cross-resistance. Options for simplified NRTI backbones include fixed-dose combinations and agents that allow once-daily dosing; however, once-daily treatment choices are currently limited because of a lack of data on potential combinations. This article provides an historical perspective on the use of NRTI backbones in the treatment of HIV infection and outlines the advantages and disadvantages of currently available backbone combinations. In addition, it provides a brief introduction to backbone combinations under investigation as potential options for initial therapy. In an environment where several NRTI/NtRTI backbones offer comparable efficacy, treatment decisions will increasingly be made based on toxicity, resistance, and convenience considerations.