The intestine has become a prime model system to study stem cell biology. Intestinal stem cells can be identified based on the expression of a unique marker gene, namely Lgr5. A transgenic mouse model expressing green fluorescent protein in intestinal stem cells has allowed their visualization, isolation, molecular characterization and use in generating organoids: small mini-guts that contain all cell types of the intestine. Detailing the behavior of intestinal stem cells has also led to new insights concerning the mechanism of self-renewal versus differentiation. Genes and pathways directing daughter cells of stem cells towards the differentiated lineages of the intestine are getting better defined. Of all differentiated cells, Paneth cells play a distinguished role: they emerged from pure bystanders to the guardians of the stem cell. Taken together, a detailed molecular picture emerges that describes the mechanisms of intestinal homeostatic self-renewal and outlines new therapeutic avenues.