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Here we provide an up-to-date review of research that explains why uncircumcised men are at higher risk of HIV infection. The inner foreskin is a mucosal epithelium deficient in protective keratin, yet rich in HIV target cells. Soon after sexual exposure to infected mucosal secretions of a HIV-positive partner, infected T-cells from the latter form viral synapses with keratinocytes and transfer HIV to Langerhans cells via dendrites that extend to just under the surface of the inner foreskin. The Langerhans cells with internalized HIV migrate to the basal epidermis and then pass HIV on to T-cells, thus leading to the systemic infection that ensues. Infection is exacerbated in inflammatory states associated with balanoposthitis, the presence of smegma and ulceration – including that caused by infection with herpes simplex virus type 2 and some other sexually transmitted infections (STIs). A high foreskin surface area and tearing of the foreskin or associated frenulum during sexual intercourse also facilitate HIV entry. Thus, by various means, the foreskin is the primary biological weak point that permits HIV infection during heterosexual intercourse. The biological findings could explain why male circumcision protects against HIV infection.