Finding a unifying concept behind the diversity of signs and symptoms in schizophrenia is a central challenge to contemporary research. A neo-Bleulerian unitary model is described, which defines the illness as a neurodevelopmentally derived "misconnection syndrome," involving connections between cortical regions and the cerebellum mediated through the thalamus (the cortico-cerebellar-thalamic-cortical circuit [CCTCC]). An abnormality in this circuitry, normally used to coordinate both motor and mental activity, leads to misconnections in many aspects of mental activity, or "cognitive dysmetria." As Bleuler originally proposed, "thought disorder" is the primary defining feature of schizophrenia, rather than the more obvious signs and symptoms such as delusions and hallucinations. Cognitive dysmetria, or a disorder in the CCTCC, may provide a heuristic theoretical framework for strategies to explore etiology, pathophysiology, intervention, or prevention.