This Perspective reviews recent findings in placebo hypoalgesia and provides a conceptual account of how expectations and experience can lead to placebo hypoalgesia. In particular, we put forward the idea that the ascending and the descending pain system resembles a recurrent system that allows for the implementation of predictive coding-meaning that the brain is not passively waiting for nociceptive stimuli to impinge on it but is actively making inferences based on prior experience and expectations. The Bayesian formulation within the predictive coding framework can directly account for differences in the magnitude but also the precision of expectations that are known to influence the strength of placebo hypoalgesia. We discuss how modulatory neurotransmitters such as opioids might be related to the characterization of expectations with an emphasis on the precision of these expectations. Finally, we develop experimental strategies that are suited to test this framework at the behavioral and neuronal level.