The Tat protein of the human immunodeficiency virus (HIV) has been implicated in the pathophysiology of the neurocognitive deficits associated with HIV infection. This is the earliest protein to be produced by the proviral DNA in the infected cell. The protein not only drives the regulatory regions of the virus but may also be actively released from the cell and then interact with the cell surface receptors of other uninfected cells in the brain leading to cellular dysfunction. It may also be taken up by these cells and can then activate a number of host genes. The Tat protein is highly potent and has the unique ability to travel along neuronal pathways. Importantly, its production is not impacted by the use of antiretroviral drugs once the proviral DNA has been formed. This article reviews the pleomorphic actions of Tat protein and the evidence supporting its central role in the neuropathogenesis of the HIV infection.