HIV-1 encodes a number of accessory proteins, which are not commonly found in other retroviruses. These proteins, which include Vif, Vpr, Vpu and Nef, act as multifunctional adapters capable of recruiting and modulating basic host cell processes to optimize wide-ranging aspects of viral replication. This review describes our current understanding of how the Vpu accessory protein functions to modulate HIV-1 particle release and CD4 receptor expression during HIV-1 infection and underlines the potential opportunities afforded by this viral protein for therapeutic intervention.