Background: The magnitude of gut adaptation may be a decisive factor in determining whether patients are able to live independent of parenteral nutrition after massive small bowel loss. We have previously established that the cyclin dependant kinase inhibitor (CDKI) p21^waf1/cip1 was necessary for enterocyte proliferation and a normal adaptation response. In this study we further elucidated the role of this CDKI in the context of p27^kip1, a second member of the Cip/Kip CDKI family. Methods: Small bowel resection (SBR) or sham operations were performed in control (C57Bl6), p21^waf1/cip1-null, p27^kip1-null, and p21^waf1/cip1 p27^kip1-double null mice. Morphologic (villus height/crypt depth) alterations in the mucosa, kinetics of enterocyte turnover (rates of enterocyte proliferation and apoptosis), and protein expression of various cell cycle regulatory proteins were recorded at various postoperative times. Cell compartment-specific mRNA expression was investigated using laser capture microdissection. Results: Resection-induced adaptation in control mice coincided with increased protein expression of p21^waf1/cip1 and decreased p27^kip1 by 3 days postoperatively. Identical changes in mRNA expression were detected in crypt, but not villus enterocytes. Adaptation occurred normally in control and p27^kip1-null mice, however mice deficient in both p21^waf1/cip1 and p27^kip1 failed to increase baseline rates of enterocyte proliferation and adaptation. Conclusion: The expression of p21 ^waf1/cip1 protein and mRNA in the proliferative crypt compartment is necessary for resection-induced enterocyte proliferation and adaptation. The finding that deficient expression of p27^kip1 does not affect adaptation suggests that these similar cdki family members display distinctive cellular functions during the complex process of intestinal adaptation.