In this review, we will discuss what is known, what is suspected, and what still remains obscure about the central role played by coreceptor expression and usage in the transmission and pathogenic consequences of human immunodeficiency virus type 1 (HIV-1) infection. An emphasis will be on the HIV-1 phenotypic variants that are defined by their usage of the CCR5 or CXCR4 coreceptors, and how the different cellular tropism of these variants influences how and where HIV-1 replicates in vivo. We will also review what might happen when coreceptor antagonists are used clinically to treat HIV-1 infection.