Vertical exposure to HIV occurs at a time when functional capacity of the infant's immune system is attenuated through immaturity. Immune response capability is rooted in host genetic makeup, and the broad and fine specificity of innate and adaptive immune responses, respectively, shape the outcomes of HIV encounter in some instances and imprint viral changes through selective immune pressure in others. Findings from recent studies have profound implications for understanding immune pathogenesis of pediatric HIV infection and, in particular, highlight the importance of host genetics of both mother and child in determining whether an exposed child acquires HIV infection or not and, if infected, the rate of disease progression. This review focuses on the key host molecules, the CC chemokine CCL3 and HLA, which have taken center stage in these new developments.