Current guidelines for treatment of human immunodeficiency virus (HIV) disease favour the use of triple-drug combinations consisting of two nucleoside analogue reverse transcriptase inhibitors (NRTIs) plus a protease inhibitor to achieve maximum suppression of HIV replication. There is considerable evidence for including one thymidine NRTI to target activated HIV host cells and one non-thymidine NRTI to target quiescent host cells as the backbone of such regimens. A number of recent studies have shown that stavudine in combination with didanosine or lamivudine is at least as effective as zidovudine-based combinations with regard to virological outcomes, with available data suggesting an enhanced effect on immunological outcome with stavudine-based combinations. When considered along with such advantageous characteristics of stavudine as infrequent and low-level resistance and good cerebrospinal fluid penetration, these findings indicate that stavudine in combination with didanosine or lamivudine should be considered for use as the backbone of multiple-agent highly active antiretroviral therapy (HAART).