The basis for using therapy with multiple mechanisms of action against an infectious pathogen capable of rapid development of resistance is not unique to HIV. For other pathogens (Mycobacterium tuberculosis, hepatitis C, Cryptococcus neoformans), multiple mechanisms of antiinfective therapy are required to achieve optimal outcomes. This basic principle and approach to therapy were found to be true in the recently published pivotal ACTG trial. The ACTG trial clearly established the improved efficacy and durability of regimens using 3 instead of 2 mechanisms of action, despite using regimens with higher pill numbers and dosing frequency, conflicting dietary requirements, and didanosine + stavudine in combination. The currently available information and published peer-reviewed studies versus data not undergoing the same level of scrutiny (conference abstracts, posters, Internet reports) justify the most recent Department of Health and Human Services guidelines that recommend therapy for antiretroviral-naïve patients consist of multiple mechanisms of action preferentially over those with mono-mechanistic combinations. Use of a mono-mechanistic regimen remains an alternative to be implemented only when absolutely necessary.