The risk of human immunodeficiency virus (HIV) transmission during sexual activity is dependent on the infectivity of the HIV-positive individual and the susceptibility of the uninfected partner. HIV is most often transmitted during periods of high HIV load, but factors such as the type of sexual activity and the innate and genetic defenses of the uninfected partner exert a strong influence on the risk of transmission. Certain factors, such as coinfection with other sexually transmitted diseases or the presence of genital lesions in either sexual partner, amplify the risk of transmission that is predicted on the basis of sexual contact alone. In the absence of more-reliable options, such as a vaccine, factors that define HIV infectivity and susceptibility and factors that amplify the risk of HIV transmission, may serve as critical targets for containment of the HIV epidemic.