© 2015 Elsevier Inc. All rights reserved. CD4+ T cells emerge from thymic selection programmed for fixed antigenic specificity. However, with the exception of natural regulatory T cells (nTreg cells), they are multipotent for alternative developmental programs that diverge contingent upon the peripheral microenvironment in which antigen is first recognized. Antigen recognition in the presence of proinflammatory cytokines elicited from antigen-presenting cells (APCs) or other innate immune cells by microbe-associated molecular patterns (MAMPs) drives the differentiation of antigen-naïve CD4+ T cells into distinct effector T cell subsets that are characterized by expression of signature cytokines that orchestrate different patterns of immunity. The intestines harbor the largest collection of CD4+ T cells in the body, including the largest number of effector T cells at homeostasis. Intestinal effector T cell responses are generally directed against antigens derived from microbes that penetrate innate barrier defenses in the gut, whether derived from the largest and most diverse commensal microbiota, or pathogenic bacteria, viruses, helminthic parasites, or fungi. In certain disease states, effector T cells can also be reactive to dietary or self-antigens. Whereas the physiologic role of effector T cell responses is pathogen eradication, when inadequately restrained or dysregulated, effector T cell responses can cause injury to host tissues and lead to chronic, immune-mediated disease.