Despite the significant advances in the knowledge and treatment of the human immunodeficiency virus (HIV) infection, it remains responsible for a worldwide epidemic. Research in macaques, using antiretrovirals as systemic pre-exposure prophylaxis (PrEP) showed encouraging results in preventing HIV transmission and led to several clinical trials in humans. In this article, we review the results of eight key PrEP studies using either tenofovir disoproxil furriarate (TDF) alone or in combination with emtricitabine (FTC): iPrEX, FEIVI-PrEP, Partners PrEP, TDF-2, VOICE, Bangkok Tenofovir Study, IPERGAY and PROUD. The results revealed that PrEP is well tolerated and its efficacy is related to adherence of the recommended regimen. The highest overall efficacy, 860Y0, was found in he IPERGAY and PROUD studies. Only one study found a suggestion of risk compensation. None of the studies identified an increase in the incidence of other sexually transmitted infections. The use of PrEP in individuals not known to be HIV-infected can increase the risk of development of drug resistance. More studies are warranted to monitor the possible long term side effects of TDF, as well as strategies to increase adherence in real life settings. Mental health professionals should be aware of PrEP and of its use.