The last two to three decades have seen substantially increased research interest in the study of the gut-brain crosstalk. This ever-expanding body of literature has demonstrated that, in addition to the previously known mechanisms through which the brain regulates gut functions, the gut itself has the ability to modulate brain functions; this influence, in turn, can affect behavior and drive neuroinflammation. Although the exact mechanisms through which the gut influences brain activities are still not completely understood, we have learned that alterations in microbiota composition and function can affect the production of the microbiome’s metabolites, which alter the gut epithelial barrier, and possibly even blood-brain barrier homeostasis. These cellular wall changes, combined with dysregulated host immune responses, may lead to changes in brain function and performance. In this review, we summarize the current evidence supporting the idea of a bidirectional gut–brain crosstalk. Most of the extant data in the literature have been obtained using germ-free animal models and/or microbiota manipulation strategies such as antibiotics, probiotics, and infections. However, clinical practice evidence in humans correlates microbiota composition alterations and/or gastrointestinal symptoms with behavioral disorders, including autism spectrum disorders, depression, and anxiety. Ultimately, improving our understanding of the mechanisms governing gut-brain interaction is critical for the design and development of novel therapies aimed at manipulating bacterial communities in an attempt to treat dysbiosis.