Reducing the incidence of HIV infection until there are no new infections depends on driving the number of secondary infections produced by a typical source infection in a completely susceptible population (basic reproduction number; R0) down to less than 1. Components of R0 that must be addressed are the number of sexual contacts the infectious person makes per unit of time (C), the probability of transmission per single sexual contact with the infectious person (P), and the duration that the infected person is infectious to others (D) (R0 = C × P × D). Numerous strategies may contribute to driving transmission of HIV infection down to zero, including early initiation of antiretroviral treatment and pre- or postexposure prophylaxis. This article summarizes a presentation by Davey M. Smith, MD, at the IAS-USA continuing education program held in San Francisco, California, in March 2015.