All-trans retinoic acid, a vitamin A metabolite, plays a key role in innate and adaptive immune responses. In this presentation,Prof Mora explains the pathways by which retinoic acid is produced by gut-associated dendritic, stromal, and intestinal epithelial cells. He also explains the role of retinoic acid for the generation of gut-tropic lymphocytes and intestinal IgA-antibody-secreting cells, and how it also modulates Foxp3+ TREG, Th1, Th2, and Th17 differentiation. Recent data show that retinoic acid is also essential for establishing oral immune tolerance. However, microbiota-specific TREG in the colon do not require retinoic acid. Short-chain fatty acids appear to play a role instead. The mechanisms governing intestinal tolerance to dietary antigens in the upper digestive tract differ substantially from those controlling tolerance to the microbiota in the colon. Both retinoic acid and short-chain fatty acids play key complementary roles in their respective compartments.