Nature Reviews Neuroscience, Published online: 23 June 2026; doi:10.1038/s41583-026-01058-w Predictive models have emerged as a normative lens for understanding neural function. In this Perspective, de Cothi, Shipley and Barry plausibly unify the diverse roles of hippocampal acetylcholine in learning and memory by proposing it serves as a fundamental learning signal, encoding the mismatch between predicted and actual environmental state transitions.