The intestinal epithelium undergoes a marked adaptive response following loss of functional small bowel surface area, characterized by increased crypt cell proliferation and increased enterocyte migration from crypt to villus tip, resulting in villus hyperplasia and enhanced nutrient absorption. Hedgehog (Hh) signaling plays a critical role in regulating epithelial-mesenchymal interactions during morphogenesis of the embryonic intestine. Our previous studies showed that blocking Hh signaling in neonatal mice results in increased small intestinal epithelial crypt cell proliferation, and altered enterocyte fat absorption and morphology. Hh family members are also expressed in the adult intestine but their role in the mature small bowel is unclear. Using a model of intestinal adaptation following partial small bowel resection, the role of hedgehog signaling in adult gut was examined by determining the effects of blocking hedgehog signaling on the regenerative response following loss of functional surface area. Hh inactivating monoclonal antibodies or control antibodies were administered to mice that sustained a 50% intestinal resection. MRNA analyses of the preoperative ileum by quantitative real time PCR, revealed that Indian hedgehog was the most abundant Hh family member. The Hh receptor Patched was more abundant than Patched 2. Analyses of downstream targets of Hh signaling demonstrated that Gli3 was 2 fold more abundant than Gli1 and Gli2 and that BMP2 was most highly expressed compared with BMP1, 4 and 7. Following intestinal resection, the expression of Hh, Patched, Gli and most BMP genes was markedly downregulated in remnant ileum, and in anti Hh antibody treated mice, expression of Ptch 2 and Gli 1 were further suppressed. In Hh antibody treated mice following resection, enterocyte migration rate from crypt to villus tip was increased, and by two weeks postop, apoptosis was increased in the adaptive gut. However, crypt cell proliferation, villus height and crypt depth were not augmented. These data indicate that Hh signaling plays a role in adult gut epithelial homeostasis, by regulating epithelial cell migration from crypt to villus tip and by enhancing apoptosis.