Abnormal decision making is a central feature of neuropsychiatric disorders. Recent investigations of the neural substrates underlying decision making have involved qualitative assessment of the cognition of decision making in clinical lesion studies (in patients with frontal lobe dementia) and neuropsychiatric disorders such as mania, substance abuse and personality disorders. A neural network involving the orbitofrontal cortex, ventral striatum and modulatory ascending neurotransmitter systems has been identified as having a fundamental role in decision making and in the neural basis of neuropsychiatric diseases. This network accounts for the dissociations among decision-making deficits in different clinical populations. Ultimately, a more refined and sophisticated characterization of such deficits might guide the early diagnosis and cognitive and therapeutic rehabilitation of these patients.