Nef is a regulatory protein expressed exclusively by HIV-1 / 2 and SIV. It is critical for the optimal viral infectivity and for the destruction of the host immune system. This renders Nef a rather attractive therapeutic target. The most affordable point(s) of attack for effective anti-Nef therapeutic strategies can be individuated on the basis of a detailed knowledge of the mechanisms underlying the Nef induced enhancement of infectivity. However, the emerging picture still appears rather complex and not always coherent, so that additional, intensive endeavours in basic research are required for an effective exploitation of the Nef induced increase of infectivity as a therapeutic target.