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The author proposes a general model of human motivation as a separate function at the interface between emotion and action, which can be ascribed to subcortical circuits that are mainly centered on a subset of the basal ganglia and on their limbic connections. It is argued that the long-standing historical understatement of the notion of motivation in neurology is not only due to the complexity of the issue, which has proven hard to disentangle from other domains of dysfunction, but also to the persistence of some misleading conceptual orientations in the way neurologists have considered the brain mechanisms of goal-directed action, torn between a nonspecific “activation” view and an exclusively cognitive conception of motivation. How combining early clinical intuitions of some psychiatrists, careful clinical observations of neurological patients, and data derived from experimental studies in animals provide the basis for a coherent model of human motivation and its specific impairment in clinical neurology is explained. Clinical implications that can be drawn from such a model for some neuropsychiatric conditions are proposed.