MyD88 is a Toll-like receptor adaptor protein that regulates intestinal homeostasis in mammals. Donna Kirkland and colleagues used cell-type-specific Myd88-deficient mice to demonstrate that B-cell-intrinsic MyD88 signaling is key to resistance to colonic damage induced by dextran sulfate sodium. MyD88 is involved in the production of IgM and complement-mediated control of intestinal bacteria. Therefore, mammals that lack functioning MyD88 signaling in B cells quickly die, as commensal bacteria become highly pathogenic in this setting.