Mucosal immune responses in the inductive lymphoid tissues of the intestine begin with uptake of particulate antigens, including components of the gut microbiota by specialized antigen sampling M cells. M cells represent a distinct lineage of enterocytes that arise from crypt stem cells in response to the cytokine receptor of NF‐κB ligand (RANKL). Full differentiation of M cells requires the transcription factor Spi‐B to yield mature M cells that express multiple receptors for bacteria including glycoprotein 2. M cell differentiation can be recapitulated in vitro using three‐dimensional enteroid cultures of primary intestinal stem cells supplemented with RANKL. This article summarizes the current knowledge about the genesis of intestinal M cells and highlights some of the remaining unanswered questions about this enigmatic cell type.