For several years, protease inhibitor ( PI)-containing antiretroviral treatment ( ART) regimens have demonstrated long-term virologic and immunologic benefits and good durability of response. However, first-generation PIs have been associated with high pill burdens, gastrointestinal side effects, perturbation of lipid levels and glucose metabolism, and, in some cases, food and hydration requirements. Coadministration of low-dose ritonavir with PIs has enhanced their pharmacokinetic profile ( lower doses, fewer pills, less frequent dosing schedules) and pharmacodynamics ( increased potency, especially against resistant viruses) but has also been associated with increases in lipid levels. Two new PIs, atazanavir and 908 (fosamprenavir), may offer salvageable PI treatment options and may also address issues of potency, tolerability, and convenience by requiring fewer pills and causing fewer lipid and glucose perturbations than current PI options. The availability of these novel PIs may improve long-term treatment options for many patients.