Apoptosis of intestinal epithelial cells (IECs) is widely recognized to play an indispensable role in maintaining gut homeostasis at steady state. Aberrant apoptosis of IEC has been documented in multiple diseases like infection, inflammatory bowel disease and colorectal cancer. In many model organisms apoptosis is also involved in regenerative processes following damage. We have developed Casp3/7ΔIEC mice that are deficient for apoptosis in IECs. Recently our lab demonstrated that at steady state in the gut absence of apoptosis can be compensated in regulation of IECs’ turnover and homeostasis, but its function in challenging conditions remains unknown (Ghazavi et al. PNAS 2022). We found already that paradoxically absence of apoptosis increases damage and inflammation in experimental colitis, suggesting an anti-inflammatory and regenerative role for the apoptotic executioner caspase-3/7. Discovery of cell-autonomous and non-autonomous effects of caspase-3/7- or apoptosis-associated processes following damage on immune and tissue repair responses will not only deepen our understanding of the biology of the gut, but also open new avenues for combating intestinal diseases, carcinogenesis and the use of caspase-inhibitors in inflammatory and degenerative diseases.