Research from Botswana as well as that from other countries indicate that the girl child is at a greater risk of HIV infection than the boy child. For example, in the context of Botswana, for every HIV-positive boy under the age of 14, there are two HIV-positive girls in the same age. This chapter discusses dynamics that account for the high vulnerability of the girl-child to HIV and AIDS in Botswana. It also highlights challenges and the way forward to combat HIV and AIDS infection among girls in Botswana.