Globally, HIV-1 is most often transmitted heterosexually so that nearly half of all infected adults are women of child-bearing age. Infants may acquire infection from vertical transmission. Without treatment most HIV-1 infected children in Africa die before their third birthday; as a result child mortality has increased overall by 35-50%, and by greater than 100% in areas of high seroprevalence. HIV-1 infection has a heterogeneous spectrum of clinical course. Compared to HIV-1-infected adults, survival times are considerably shorter for children who acquire the virus perinatally or during infancy. Factors contributing to accelerated disease progression in infants and children are poorly understood but may include relative immunological immaturity, thymic HIV-1-mediated destruction at a time of active thymopoiesis, and HLA class I sharing between mother and infant. This review will initially discuss clinical and biological determinants of mother-to-child transmission and disease progression in HIV-infected infants and children. Our current knowledge of the mechanisms of T cell depletion is summarised and the host immune response to HIV-1 (innate and adaptive) described in the context of Pediatric HIV-1 infection.