In this review, incorporating functional and structural MRI and DTI, with evidence gathered over the last 15 years, we examine the neural underpinnings of extraversion and neuroticism, the two major personality dimensions in Eysenck's (1967) biological model of personality. We present clear evidence that, as proposed by Eysenck nearly half-a-century ago, these traits relate meaningfully to the functioning and structure of various cortical and limbic brain regions. Specifically, there is a robust relationship between neuroticism and the functioning of several emotion processing networks in the brain, particularly during exposure to negative stimuli. The brain regions showing this association include a number of cortical regions implicated in emotion regulation, depression and anxiety, in addition to many sub-cortical/limbic regions. Currently, there are few studies directly assessing the relationship between extraversion and the cortical arousal system in the context of varying stimulations but data available so far are remarkably consistent with Eysenck's model. Future neuroimaging studies guided by relevant personality and cognitive theories, and with sufficient power to allow application of sophisticated analysis methods (for example, machine learning) are now needed to improve our understanding of the biological basis of individual differences and its application in the promotion of well-being and mental health.