In the second decade of highly active antiretroviral therapy, drug regimens offer more potent, less toxic and more durable choices. However, strategies addressing convenient sequential use of active antiretroviral combinations are rarely presented in the literature. Studies have seldom directly addressed this issue, despite it being a matter of daily use in clinical practice. This is, in part, because of the complexity of HIV-1 resistance information as well as the complexity of designing these types of studies. Nevertheless, several principles can effectively assist the planning of antiretroviral drug sequencing. The introduction of tenofovir disoproxil fumarate, abacavir and emtricitabine into current nucleoside backbone options, with each of them selecting for an individual pattern of resistance mutations, now permits sequencing in the context of previously popular thymidine analogues (zidovudine and stavudine). Similarly, newer ritonavir-boosted protease inhibitors could potentially be sequenced in a manner that uses the least cross-resistance prone protease inhibitor at the start of therapy, while leaving the most cross-resistance prone drugs for later, as long as there is rationale to employ such a compound because of its utility against commonly observed drug-resistant forms of HIV-1.