CCR5 antagonists disrupt crucial interactions between HIV envelope glycoprotein gp120 and CCR5, preventing virus binding and entry. Current antiretroviral agents target viral proteins, whereas CCR5 antagonists bind to the host cell. This novel mechanism of action is posing new challenges to our understanding of drug resistance.Possible mechanisms of resistance to CCR5 antagonists include the selection of CXCR4-tropic variants and the continued use of CCR5. Recent in-vitro data suggest that true co-receptor 'switch' may require the sequential accumulation of multiple mutations, and the emergence of CXCR4-using virus in some individuals during short-term CCR5 antagonist monotherapy generally appears to result from the outgrowth of pre-existing CXCR4-using variants. Some degree of resistance with continued CCR5 use is possible if viruses develop an increased affinity for unbound CCR5 molecules, characterized phenotypically by a classic shift in the 50% inhibitory concentration. Growing in-vitro evidence, however, identifies an alternative pathway to resistance - one in which the virus acquires the ability to use compound-occupied receptors, and is characterized by dose-response curves with plateaus at less than 100% maximal inhibition.New ways of interpreting phenotypic resistance data may be required for these agents. This will be aided by a consideration of receptor pharmacology rather than enzyme kinetics.