Prevention of mother-to-child transmission of HIV is a significant public health priority. A regimen of zidovudine administered during pregnancy, intrapartum, and to the newborn significantly reduces transmission, and incorporation of this regimen into clinical practice has been associated with significant decreases in perinatal transmission in industrialized countries. This regimen, however, is not applicable in the developing world (where most perinatal transmission occurs), and simpler, shorter, less costly regimens are urgently needed. An understanding of the pathogenesis of perinatal transmission is crucial for the design of new preventive and therapeutic regimens, and current knowledge is reviewed in this article, with an emphasis on relevance to prevention.