Intestinal homeostasis and regeneration rely on intestinal stem cells (ISCs). Li et al. identified neuronal vasoactive intestinal peptide (VIP) as a brake on ISCs through VIPR1 to limit regeneration. In Nature Immunology, Jakob et al. and Pirzgalska et al. further showed that VIP-VIPR1 signaling restrains secretory lineage expansion and balances immune responses.