The benefit of recombination to HIV remains unclear because just as recombination can induce the association of favorable mutations and accelerate the development of multidrug resistance, it can also dissociate favorable combinations of mutations. The confounding influences of mutation, random genetic drift, selection and epistatic interactions between multiple resistance loci render the role of recombination difficult to unravel experimentally. Mathematical models provide valuable insights into the influence of recombination on the genomic diversification of HIV and the development of drug resistance in patients undergoing therapy, capture several recent experimental observations of HIV recombination quantitatively, and set the stage for the establishment of a robust framework for the identification of improved treatment protocols and guidelines for drug development.