In the past 15 years, improvements in the treatment of HIV infection have dramatically reduced morbidity and mortality. Nucleoside reverse transcriptase inhibitors are the backbone of combination antiretroviral therapy for the treatment of HIV. One of the recommended and commonly used therapies in this class is the once-daily fixed-dose combination of abacavir/lamivudine. Clinical studies and practice have shown these drugs to be potent, safe, and easy to use in a variety of settings; however, several recent reports have challenged the safety and efficacy claims among certain patient populations, including those at risk for cardiovascular disease and in those with high viral loads prior to treatment initiation. We reviewed abacavir/lamivudine as a treatment for HIV and discussed limitations of its use due to these controversial issues.