A comparative and integrated account is provided of the evidence that implicates frontostriatal systems in neurodegenerative and neuropsychiatric disorders. Specifically, we have made detailed comparisons of performance following basal ganglia disease such as Parkinson's disease, with other informative groups, including Alzheimer's disease, schizophrenia and attention deficit/hyperactivity disorder and structural damage to the frontal lobes themselves. We have reviewed several behavioural paradigms including spatial attention and set-shifting, working memory and decision-making tasks in which optimal performance requires the operation of several cognitive processes that can be successfully dissociated with suitable precision in experimental animals. The role of ascending neurotransmitter systems are analysed from the perspective of different interactions with the prefrontal cortex. In particular, the role of dopamine in attentional control and spatial working memory is surveyed with reference to its deleterious as well as facilitatory effects. Parallels are identified in humans receiving dopaminergic medication, and with monkeys and rats with frontal dopamine manipulations. The effects of serotonergic manipulations are also contrasted with frontal lobe deficits observed in both humans and animals. The main findings are that certain tests of frontal lobe function are very sensitive to several neurocognitive and neuropsychiatric disorders. However, the nature of some of these deficits often differs qualitatively from those produced by frontal lobe lesions, and animal models have been useful in defining various candidate neural systems thus enabling us to translate basic laboratory science to the clinic, as well as in the reverse direction.