Although oral tolerance is the normal physiologic response to ingested antigens, a breakdown in this process appears to have occurred in the past 2 decades, leading to an increasing prevalence of sensitization to food allergens. Over the past decade, basic research has intensified in an attempt to better understand the mechanisms leading to sensitization and disease versus desensitization and short- and long-term tolerance. In this review we assess various factors that can influence tissue and immune responses to food antigens, the current understanding of immune tolerance development, the role of the gastrointestinal microbiota, and current knowledge regarding immunologic mechanisms involved in desensitization and sustained unresponsiveness, although perhaps the latter is more appropriately termed remission.