Crohn’s disease and ulcerative colitis are collectively known as inflammatory bowel disease (IBD), which is a condition characterized by chronic inflammation of the gastrointestinal tract. Analyses of patients with IBD and animal models of chronic colitis have facilitated the understanding of the immunopathogenesis of IBD. These studies evidence that a decrease in regulatory T cells’ (Tregs) number and function are associated with the onset and development of disease. In the intestine, the major function of Treg is to regulate inflammation and establish tolerance to nonpathogenic antigens including those found in commensal bacteria and food. Because of their multiple suppressive mechanisms and accumulation in the gut-associated lymphoid tissue, Tregs represent a promising strategy for engineering immune tolerance to dietary and gut microbiota antigens that lead to IBD. In this chapter, we explore the role of Treg, cytokines, and microbiome in the pathogenesis of IBD. The chapter discusses the main types of intestinal Treg and their immunomodulatory mechanisms. Finally, we have also presented data from preclinical and clinical studies investigating the efficacy of Treg therapies in the context of IBD.