N, N-dimethyltryptamine (DMT) is an indole alkaloid produced by a number of plants and animals, including humans. Its psychoactive effects were first described in 1956 by Stephen Szára, but have been exploited for centuries by South American indigenous populations throught the use of ayahuasca, an infusion made with a mixture of plants rich in the psychadelic DMT. In the present review, we assess the state of the art regarding a putative role for endogenous DMT and potential future clinical applications. We gathered papers published until 20 March 2018 and included in the PubMed database using the words: N,Ndimethyltryptamine and ayahuasca. While the role of endogenous DMT remains unclear, ayahuasca has promising results in anxiety, depression and substance dependence. Thus, we conclude that although little has been proven, much has been speculated about the endogenous role of DMT. Overcoming the methodological setbacks is crucial to develop research further. In the other hand, ayahuasca has a good safety profile and growing evidence it could be used in therapy for some neuropsychiatric diseases.