Reduced apoptosis of crypt stem/progenitor cells and elevated insulin and insulin-like growth factors (IGFs) are linked to colon cancer risk. Insulin receptor substrate-1 (IRS-1) mediates the actions of insulin, IGF-I, and IGF-II, but the role of endogenous IRS-1 in crypt apoptosis and cancer is undefined. Using IRS-1^-/-, IRS-1^+/-, and IRS-1^+/+ mice, we tested the hypothesis that reduced IRS-1 expression increases apoptosis of intestinal crypt cells and protects against Apc^min/+ (Min)/-catenin-driven intestinal tumors. Expression of Sox9, a transcriptional target of Tcf/-catenin and putative biomarker of crypt stem cells, was assessed in intestine of different IRS-1 genotypes and cell lines. Irradiation-induced apoptosis was significantly increased in the crypts and crypt stem cell region of IRS-1 deficient mice. Tumor load was significantly reduced by 31.2 ± 14.6% in IRS-1^+/-/Min and by 64.1 ± 7.6% in IRS-1^-/-/Min mice, with more prominent reductions in tumor number than size. Compared with IRS-1^+/+/Min, IRS-1^-/-/Min mice had fewer Sox9 positive cells in intestinal crypts and reduced Sox9 mRNA in intestine. IRS-1 overexpression increased Sox9 expression in an intestinal epithelial cell line. We conclude that even small reductions in endogenous IRS-1 increase apoptosis of crypt stem or progenitor cells, protect against -catenin-driven intestinal tumors, and reduce Sox9, a Tcf/-catenin target and putative stem/progenitor cell biomarker of putative crypt stem/progenitor cells.