The possible neural and neurochemical bases of the hubris syndrome are reviewed by considering relevant evidence from behavioural and cognitive neuroscience in relation to biological psychiatry. This multidisciplinary evidence includes studies of brain-damaged patients and functional neuroimaging and identifies the prefrontal cortex as a crucial region of a brain network undertaking decision-making. The prefrontal cortex is also identified as important for the subjective and behavioural expression of relevant personality traits such as narcissism and impulsivity. Factors that adversely affect so-called executive functions of the prefrontal cortex, such as stress, drug abuse and illness, are also taken into account to highlight possible neurochemical and endocrine influences. A novel hypothesis is presented which postulates a key role for the chronic stress of leadership status depleting monoamine neurotransmitters such as serotonin, dopamine and noradrenaline, which interact with pre-existing temperamental traits, to produce dysfunctional modulation of decision-making circuits controlled by the ventromedial prefrontal cortex