In recent years there has been a paradigm shift in theoretical neuroscience in which the brain-as a passive processor of sensory information-is now considered an active organ of inference, generating predictions and hypotheses about the causes of its sensations. In this commentary, we try to convey the basic ideas behind this perspective, describe their neurophysiologic underpinnings, and highlight the potential importance of this formulation for clinical neuroscience. The formalism it provides-and the implementation of active inference in the brain-may have the potential to reveal aspects of functional neuroanatomy that are compromised in conditions ranging from Parkinson disease to schizophrenia. In particular, many neurologic and neuropsychiatric conditions may be understandable in terms of a failure to modulate the postsynaptic gain of neuronal populations reporting prediction errors during action and perception. From the perspective of the predictive brain, this represents a failure to encode the precision of-or confidence in-sensory information. We propose that the predictive or inferential perspective on brain function offers novel insights into brain diseases.