Adverse reactions to dietary proteins (DPs) can impose a significant impact on one's daily life and can even affect the 'life style' of an entire family. Adverse reactions to DPs may or may not be immune-mediated. The immune-mediated adverse reaction to food is defined as food allergy (FA) which is roughly divided into IgE mediated or non-IgE mediated FA (NFA). As opposed to IgE mediated FA, NFA primarily affects the GI mucosa. In addition, there is far less of an understanding of NFA than IgE-mediated FA and its clinical relevance is likely under-estimated in most cases. This is partly due to delayed onset of symptoms and subsequent difficulty in making the clinical association between offending food and clinical symptoms. The lack of easily accessible diagnostic measures also contributes to the problem. The gut mucosal barrier is thought to have developed to execute an immensely difficult task; digestion and absorption of nutrients without provoking immune responses and cohabiting with commensal flora in a mutual beneficial relationship, while maintaining an immune defense against pathogenic microbes. The gut mucosal immune system accomplishes this task partly by establishing tolerance to macronutrients with potent immunogenecity. Immune tolerance to macronutrients (DPs) is maintained in part by active suppressive mechanisms involving antigen (Ag)-specific regulatory T (Treg) cells. This active immune tolerance state appears to be affected by various environmental factors such as change in commensal flora. In the first few years of life, humans gradually develop an intricate balance between tolerance and immune reactivity in the gut mucosa along with a tremendous expansion of gut associated lymphoid tissue (GALT). Not surprisingly, both IgE and non-IgE mediated food allergy (FA) is frequently seen during this period. The most common causative DPs for NFA are those contained in infant formulas (cow's milk and soy proteins). Unlike IgE mediated FA, NFA is rarely life-threatening. However, NFA to DPs can cause significant morbidity in rapidly growing infants and young children. A better understanding of pathogenesis of NFA is crucial for timely management of NFA in this vulnerable population. This review discusses the gut mucosal immune system in the first few years of life including genetic/environmental factors affecting the development of mucosal immune system and pathogenesis of NFA in association with clinical/laboratory findings.