This review summarizes how interleukin-10 (IL-10)-deficient mice have permitted new insight into the complex interaction between genes and environment underlying pathogenesis of inflammatory bowel disease (IBD). The C57BL/6J strain develops only mild typhlocolitis in response to IL-10 deficiency. In contrast, C3H/HeJBir represents an unrelated inbred strain with high IBD susceptibility. Ability to identify quantitative trait loci segregating for susceptibility when the two IL–10-deficient stocks were intercrossed depended both on genome “context” (F2 versus reciprocal backcrosses) and on the physical environment. These findings are discussed in the context of recent advances in understanding the complex genetic basis for IBD in humans.