Mother-to-child transmission (MTCT) of HIV continues to fuel the worldwide pediatric HIV epidemic. Without any intervention to prevent transmission, the rate of MTCT of HIV is estimated at 12-40%. The prevalence of pediatric HIV infection in a given community is the sensor for both the magnitude and the trajectory of the HIV epidemic in that community. A myriad of viral and host risk factors act in tandem to cause MTCT of HIV. In this review, the mechanisms, timing of transmission, and risks factors (i.e. viral and host) associated with MTCT of HIV are discussed. Although significant declines in MTCT have been achieved in both resource-rich and resource-limited countries over time, there are still challenges and threats that have the potential to reverse the gains made so far. Understanding the mechanisms, timing, and viral and host factors associated with MTCT of HIV will help to identify appropriate interventions and suitable antiretroviral chemoprophylaxis regimens to reduce or eliminate MTCT.