The major HIV-1 coreceptors, CCR5 and CXCR4, mediate virus entry into CD4+ cells and are therefore a critical component of the HIV-1 life cycle. Alterations in coreceptor preference as well as the efficiency and mechanism of interaction between HIV-1 and CCR5 and/or CXCR4 has a significant influence on viral tropism, progression of disease, and response to coreceptor antagonists. In addition, these alterations influence the susceptibility of CD4+ T-cell, monocyte, and dendritic cell subsets to infection and therefore, are important for several facets of HIV-1 pathogenesis including the establishment of latent reservoirs, trafficking, and transmission. This review highlights recent literature that has advanced our understanding of the role of coreceptors in HIV-1 pathogenesis.