The onset and reversibility of major depression is likely to be explained by diffuse neuromodulatory mechanisms rather than permanent abnormalities of connectivity and neurotransmission. However, the expression of mood state appears to involve fronto-striatal mechanisms. Lesions of the ventral frontal cortex give rise to profound modification of affect and behaviour not explained by effects on current intellectual function. These may represent the most extreme possible disturbances of emotional experience. Neuropsychological testing in major depression shows evidence of slowing in motor and cognitive domains with additional prominent effects on mnemonic function most marked in the elderly. Structural imaging with X-ray computed tomography or magnetic resonance imaging in older patients with major depression shows evidence of structural abnormality compared with controls. These findings are not highly localizing but they tend to confirm the role of cognitive impairment as an important age-related risk factor for major depression. Perfusion or metabolic imaging reflects both reversible changes in function and permanent loss of active neurones. The usual finding has been reductions in anterior brain structures in major depression. Hypoperfusion tends to be greatest in frontal, temporal and parietal areas and most extensive in older (male) patients; high Hamilton scores tend to be associated with reduced uptake. There have also been correlations in the cingulate cortex between increased perfusion and other aspects of the mental state. In general, reductions in frontal areas may be more likely in patients with impoverished mental states. The more prominent impairments of memory are likely to be associated with the finding of impaired temporal function or with a more diffuse failure of neuromodulation.