The turnover of intestinal epithelial cells is a finely regulated process extending from undifferentiated crypt stem cells to terminally differentiated villus cells. The final phase of this maturation process is apoptosis and extrusion. Recent studies have shown that programmed cell death (PCD) occurs not only in senescent cells and in rapidly developing tissues but also in response to cellular stress preventing damaged cells from entering uncontrolled proliferation without repair. This study examined the role of exogenous nucleotides on cell proliferation, differentiation and apoptosis in organ cultures of human fetal small intestine. The addition of adenosine monophosphate (AMP), a putative stress reactant, to the culture media resulted in the suppression of crypt cell proliferation followed by the restoration of differentiation and the induction of apoptosis across a broad range of villus epithelium when compared with controls without added nucleotide. In contrast, the addition to cytidine monophosphate (CMP) to the culture media did not increase apoptosis, despite the nucleotide being taken up by the fetal small intestine in a similar dose- and time-dependent manner to AMP. Furthermore, Bax mRNA, an apoptosis-inducer gene, was increased with addition of AMP, suggesting that the induction of apoptosis may be channeled through the p53 pathway. These results suggest that a specific exogenous nucleotide, AMP, may have an important role in controlling the dynamic balance of cellular turnover in the developing human small intestine.