Vpx is coded almost exclusively by members of the SIVSM/HIV-2 lineage of primate lentiviruses, it is incorporated into virion particles and is thus present during the early phases of infection of target cells. While Vpx exerts no detectable function during the infection of most cell types, it potently counteracts a cellular restriction that targets incoming lentiviruses specifically in myeloid cells. As a consequence of this function, Vpx improves the efficiency of lentiviral infection of dendritic cells (DCs), macrophages, and monocytes. Here, we describe how the positive function exerted by Vpx during the early phases of infection of myeloid cells can be used to augment the efficiency of lentiviral vector-mediated gene transfer in these cells.