Anxiety disorders are among the most prevalent psychiatric disorders, having a lifetime prevalence of around 17%. Social anxiety disorder (SAD), or social phobia, is the most common type of anxiety disorder, being the third most frequent psychiatric disorder, with a lifetime prevalence that can reach 15%. Pharmacological treatments have limited efficacy and are associated with significant adverse reactions. Thus, new treatments should be investigated. Preclinical and clinical evidence suggest that ayahuasca, a botanical hallucinogen rich in the β-carboline harmine and in the tryptamine dimethyltryptamine (DMT), has anxiolytic properties. Moreover, there is also clinical evidence that other hallucinogens that share a similar mechanism of action with ayahuasca/DMT (agonism at cortical serotonin 5-HT1A/2A/2C receptors), such as lysergic acid diethylamide (LSD) and psilocybin (from “magic mushrooms”), also have anxiolytic properties. In the present article, we review basic and clinical evidence supporting the possible beneficial effects of ayahuasca (and other serotonergic or classical hallucinogens) in the treatment of mood and anxiety disorders in general, with a focus on social anxiety. We also review neuroimaging studies showing that these compounds modulate brain areas involved in emotion processing, and describe the fast and sustained anxiolytic and antidepressive effects of ayahuasca in patients with treatment-resistant major depressive disorder recently reported by our group. Finally, we integrate the preclinical and clinical evidence (translational approach) concluding that there is significant evidence to explore the potential anxiolytic effects of ayahuasca in patients with SAD, and briefly comment on our ongoing double-blind, placebo-controlled, crossover study of ayahuasca in socially anxious individuals.