CD4+ T cells are essential for development and perpetuation of Crohn’s disease, a chronic immune-mediated condition that affects primarily the small intestine. Using novel models of Crohn’s disease-like ileitis (ie, SAMP1/YitFc and CD4+ T cell transfer models), we have begun to understand the adhesive pathways that mediate lymphocyte trafficking to the chronically inflamed small bowel. Expansion of the CD4/β 7+ population and increased mucosal addressin cell adhesion molecule-1 (MAdCAM-1) expression were observed within the intestinal lamina propria with disease progression. However, Ab blockade of the β 7 integrin, the α 4 β 7 heterodimer, MAdCAM-1, or L-selectin did not attenuate inflammation. Blockade of two pathways (L-selectin and MAdCAM-1 or α 4 integrins) was required to improve ileitis. Further analyses showed that 55±7% of the mesenteric lymph node α 4 β 7+ CD4 expressed L-selectin. These L-selectin+ T cells were the main producers of TNF-α and the predominant ileitis-inducing subpopulation. Mechanistically, combined blockade of L-selectin and MAdCAM-1 depleted the intestinal lamina propria of CD4+ T cells that aberrantly coexpressed α 4 β 7 and α 4 β 1 integrins, markedly decreasing local production of TNF-α and IFN-γ. Thus, pathogenic CD4+ T cells not only use the physiologic α 4 β 7/MAdCAM-1 pathway, but alternatively engage α 4 β 1 and L-selectin to recirculate to the chronically inflamed small intestine.