Major depressive disorder (MDD) is generally classified as a mood disorder with a profound effect on the individual’s behavior and quality of life. According to the World Health Organization, in about 20 years, depression will be the disorder with the most significant repercussions, both socially and economically. Despite the substantial progress in the development of new antidepressants, their effectiveness remains low, with remission of about 50 % after a single regime of treatment. The most common form of pharmacological treatment of MDD is based on selective serotonin reuptake inhibitors (SSRIs), designed to increase extracellular levels of the neurotransmitter serotonin. Unfortunately, antidepressants currently available based on SSRIs may take several weeks to achieve the desired therapeutic effects. Therefore, massive effort has been devoted to find alternative treatments for MDD. For example, the use of ketamine, of (±)-1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane (DOI), and β-carbolines is under current investigation. Based on evidence from the literature and a pilot study conducted by our group, we speculate about the possible therapeutic potential of ayahuasca for MDD. In part, such conjecture is based on the fact that ayahuasca combines N,N-dimethyltryptamine (DMT), acting particularly on serotonin neurotransmission through 5-HT2A receptors and monoamine oxidase inhibitors (MAOI), both involved, at least indirectly, with pharmacological formulations intended for MDD treatment. In this chapter, we will review the major aspects of MDD such as diagnosis, current pharmacological treatments, and the motivations to use ayahuasca as a novel alternative.