Since these early days, therapies have evolved, with the introduction of newer drugs with greater potency and higher barriers to the development of resistance. Moreover, some antiretroviral agents have been shown to select for mutations which are either incompatible with or engender hypersensitivity to other antiretroviral drugs, suggesting certain ARVs may offer an advantage with respect to resistance barrier when used in the context of specific combinations (Larder et al. 1995; Kempf et al. 1997; Hsu et al. 1998). Therefore, whether HIV-1 treatment can be simplified to two or even one potent drug(s) remains an open question that can only be answered with future clinical studies.