Human immunodeficiency virus (HIV) coreceptor-usage or “tropism” is an area of intensive research because of the association of tropism with immunological decline and the advent of chemokine receptor (CCR)5-antagonist medications. Most early infections are caused by HIV variants that use the CCR5 coreceptor, but over the course of infection, variants using the CXCR4 coreceptor can emerge. This phenomenon, referred to as coreceptor or tropism switching, may occur for a variety of reasons. This process and the possible explanations are discussed in this issue of HIV Medical Update.