The replication of human immunodeficiency virus type 1 (HIV-1) in non-dividing cells, such as terminally differentiated macrophages, critically depends on the import of the viral pre-integration complex (PIC) into the nucleus. Vpr, one of the accessory gene products of HIV-1, plays a key regulatory role in PIC nuclear import in macrophages, although its role in the PIC entry mechanism remains to be clarified. Here, we summarize what is currently known about the nuclear-entry step of HIV-1 replication, mainly focusing on how Vpr functions as the main regulator of HIV-1 nuclear import and how it could facilitate the development of novel inhibitors of this process.