Defining the mechanisms of HIV-1 entry has enabled the rational design of strategies aimed at interfering with the process. This article delineates what is currently understood about HIV-1 entry, as a window through which to understand what will likely be the next major group of antiretroviral therapeutics. These exciting new approaches offer the promise of adding viral entry to reverse transcription and protein processing as steps to block in the viral life cycle. Several principles learned with other antiretroviral drugs are sure to be valid for entry antagonists, whereas other considerations may be unique to this group of agents. There is no agent to which HIV-1 has not been able to acquire resistance and this is likely to remain the case. Multiple rounds of viral replication are required to generate the genetic diversity that forms the basis of resistance. Combination therapy in which replication is maximally suppressed will remain a cornerstone of treatment with entry inhibitors, as with other agents. Furthermore, the coreceptor specificity of some entry and fusion inhibitors argues that combinations will likely be needed to broaden the effective range of susceptible viral variants. Finally, the targeting of multiple steps within the entry process has the potential for synergy. The fusion inhibitor T20 and CXCR4 antagonist AMD3100 are synergistic in vitro at blocking infection of PBMC with clinical isolates [115] and T20 combined with the CD4 inhibitor PRO 542 have synergistic in vitro effects, with more than 10-fold greater inhibition of R5, X4, and R5X4 strains than either agent alone [116]. Entry antagonists raise other, unique issues. As discussed previously, the theoretic concern exists that blocking CCR5 could enhance the emergence of CXCR4-using variants and possibly accelerate disease. So far, in vitro selection for variants resistant to the CCR5 antagonist SCH-C in PBMC (which express both CCR5 and CXCR4) has resulted in mutants that were resistant to the blocker but still used CCR5. Alternatively, because many HIV-1 strains have the capacity to use several other chemokine or orphan receptors for entry, blocking both CCR5 and CXCR could lead to a variant that uses one of these other molecules in place of the principal coreceptors, although data in vitro so far suggest that this is unlikely [13,14]. This new class of antiviral drugs offers great promise but also novel concerns, and careful analysis of viruses that arise with their use in vivo is essential.