The lumen of the gastrointestinal tract is exposed daily to an array of dietary proteins. The vast majority of proteins are tolerated through suppression of cellular or humoral responses, a process known as oral tolerance. However, in approximately 6% of children and 4% of adults in the United States, tolerance to a given dietary antigen either is not established or breaks down, resulting in food hypersensitivity. Although food allergies can result in sudden and life-threatening symptoms, their prevalence is remarkably low considering the complexities of the gut-associated mucosal system. Suppression involves signaling by an array of nonprofessional antigen-presenting cells, dendritic cells, and regulatory T cells, as well as lymphocyte anergy or deletion. Several factors, including antigen properties, route of exposure, and genetics and age of the host, contribute to the development of oral tolerance. Although the current standard of care for patients with food allergies is based on avoidance of the trigger, increased understanding of the mechanisms involved in tolerance has shifted focus of treatment and prevention toward inducing tolerance. Data from early-phase clinical trials suggest both sublingual and oral immunotherapy are effective in reducing sensitivity to allergens. In this article we review the mechanisms of tolerance, discuss aberrations in oral tolerance, and provide information on novel prevention and treatment paradigms for food allergy.