To delineate the fundamental aspects of HIV-1 in genital secretions such as virus origins, dynamics, and modifiable factors and their effects on viral reservoirs in the male and female genital compartments.The transmission rate of HIV-1 per sexual encounter is relatively small. Male and female genital tissues secrete distinct cell-free and cell-associated HIV-1 quasispecies that are different from the populations present in the blood. Cell-free and cell-associated HIV-1 in the genital compartment originates from discrete tissues in the male and female genital regions rather than from the blood. Recent findings indicate that compartmentalization is maintained through immune response pressures on viral selection. HIV-1 clearance rates after therapy, and thus HIV-1 replication, in the male genital organ is slower than that in blood. Furthermore, higher concentrations of latently infected cells are found in the semen compartment compared with the blood compartment.Viral populations in genital tissues respond to therapy differently to those present in blood. This would suggest that the genital and blood compartments probably serve as distinct reservoirs harboring latent HIV-1 during prolonged drug therapy. Understanding transmission at these sites, as well as the different viral and environmental replication characteristics and the tissue sites of virus origin in these compartments is vital to creating better treatment and prevention regimens.