The human immunodeficiency virus (HIV-1) (transactivator of transcription (Tat)) protein is a pleiotropic factor that induces a broad range of biological effects in numerous cell types. At the HIV promoter, Tat is a powerful transactivator of gene expression, which acts by both inducing chromatin remodeling and by recruiting elongation-competent transcriptional complexes onto the viral LTR. Besides these transcriptional activities, Tat is released outside the cells and interacts with different cell membrane-associated receptors. Finally, extracellular Tat can be internalized by cells through an active endocytosis process. Here we discuss some of the molecular mechanisms involved in intracellular and extracellular Tat function.