Acetylcholinesterase (AChE) is a highly conserved protein that is known for its essential role in degrading the neurotransmitter acetylcholine at neural synapses. However, it is expressed more broadly, outside the nervous system, suggesting that it may carry out additional functions. Now, on p. 2764, Nanette Nascone-Yoder and colleagues reveal that AChE plays an essential non-classical role in Xenopus gut morphogenesis. By exposing tailbud stage Xenopus embryos to AChE inhibitors, or by injecting embryos with morpholinos to knock down AChE in the intestinal endoderm, they show that AChE is required for proper intestinal morphogenesis; in the absence of AChE function, intestines are short/malrotated and exhibit a disorganised epithelium. This function of AChE , they report, is independent of its cholinesterase activity. Further analyses demonstrate that AChE is required for endoderm cell rearrangement and polarisation – events that drive gut lengthening and morphogenesis – as well as endoderm cell differentiation. Finally, the researchers demonstrate that AChE regulates cell-substrate but not cell-cell adhesion. Overall, these results provide direct in vivo evidence for a morphogenetic function for AChE in non-neuronal tissues and suggest that AChE may function in other aspects of development and physiology, a find that has important implications given the widespread use of cholinesterase inhibitors in the treatment of human diseases.