CD4+ T cells and tissue macrophages are well defined as the major targets for human immunodeficiency virus type 1 (HIV-1) infection and replication, and their infection accounts for many aspects of HIV-1 pathogenesis in vivo. HIV-1 genotype and phenotype in monocytes and their potential roles in pathogenicity in vivo remain unknown. Herein is an overview of our initial work on HIV-1 genotype in purified CD14+ monocytes isolated longitudinally during the course of infection starting from the time of infection. Our data provide evidence for HIV-1 evolution in monocytes and their role as a reservoir of HIV-1 in vivo. A better understanding of HIV-1 in monocytes may greatly help the development of new therapeutic strategies for HIV-1 infection.