The severe combined immunodeficiency (SCID) model of colitis shares many features of idiopathic inflammatory bowel disease (IBD) in humans. The SCID model is highly reproducible and easily manipulated, and as such provides a useful tool for studying mucosal immune regulation as it relates to the pathogenesis and treatment of IBD in humans. This unit describes a cell transfer system in which SCID mice are reconstituted with CD4⁺ CD45RB^high cells to induce IBD. The CD4⁺ cells are isolated by immunomagnetic negative selection using monoclonal antibodies, and are then separated by fluorescent cell sorting into CD45RB^high and CD45RB^low cells. The former population reproducibly induces disease in recipients. A support protocol describes methods to monitor disease progression, which is characterized by weight loss, loose stools, and histologically assessed lesions in the colon.