The mucosal immune system mediates contact between the host and the trillions of microbes that symbiotically colonize the gastrointestinal tract. Failure to tolerate the antigens within this “extended self” can result in inflammatory bowel disease (IBD). Within the adaptive immune system, the most significant cells modulating this interaction are Foxp3⁺ regulatory T (T_reg) cells. T_reg cells can be divided into 2 primary subsets: “natural” T_reg cells and “adaptive” or “induced” T_reg. Recent research suggests that these subsets serve to play both independent and synergistic roles in mucosal tolerance. Studies from both mouse models and human patients suggest that defects in T_reg cells can play distinct causative roles in IBD. Numerous genetic, microbial, nutritional, and environmental factors that associate with IBD may also affect T_reg cells. In this review, we summarize the development and function of T_reg cells and how their regulatory mechanisms may fail, leading to a loss of mucosal tolerance. We discuss both animal models and studies of patients with IBD suggesting T_reg cell involvement in IBD and consider how T_reg cells may be used in future therapies.