The human immunodeficiency virus (HIV) enters target cells via interaction of the viral glycoprotein with the cellular receptor CD4 and two principal coreceptors, CCR5 (R5 viruses) and CXCR4 (X4 viruses). Most HIV-1 transmissions result in a predominantly R5 virus infection. With time, X4 variants arise and coexist with R5 virus variants in ∼50% of subtype B infected individuals. The underlying basis for virus coreceptor switch late in infection remains an enigma, but will be important to understand given that the appearance of X4 virus in HIV-1 infected patients inevitably heralds an unfavorable clinical outcome. Recently, emergence of X4 viruses was observed in rhesus macaques experimentally infected with a CCR5-tropic simian-human immunodeficiency virus (SHIV) with progression to disease, providing some insights into the process of coreceptor switching in vivo. Further studies in this animal model should enhance our understanding of the mechanistic basis for, and obstacles to, coreceptor switch.