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To discuss the recent landmark findings that have increased our understanding not only of the role of the epithelial cell cycle in the homeostasis of the small intestine, but also its relevance to inflammation and cancer.Recent data have unveiled novel information on protein interactions directly involved in the cell cycle as well as in the pathways that transduce external environmental signals to the cell cycle. A growing body of the recent evidence confirms the importance of food as well as hormonal regulation in the gut on cell cycle. Information on the contribution of the epithelial microenvironment, including the microbiota, has grown substantially in the recent years as well as on the gene–environment interactions and the multiple epigenetic mechanisms involved in regulating cell-cycle proteins and signalling. Finally, further studies investigating the dysregulation of the cell cycle during inflammation and proliferation have increased our understanding of the pathophysiology of chronic inflammatory diseases and cancer.This review highlights some of the most recent advances that further emphasize the importance of the cell cycle in the small intestine during homeostasis as well as in inflammation and cancer.