For most of human evolutionary history our species lived as hunter-gatherers; hence, much of our cognition and behaviour is adapted to this way of life. Given the magnitude of the sociocultural, economic and lifestyle changes experienced by Homo sapiens over the last 10,000 years, in particular the last several hundred years, aspects of human psychology may be maladapted to modern ways of life. This process of maladaptation following changes in the physical or social environment is referred to as ‘evolutionary mismatch’ and has been hypothesised to contribute to the high prevalence of mental disorders in industrialised societies. However, very few studies have examined the prevalence of these pathologies among contemporary hunter-gatherer populations; thus, empirical support for such diseases of modernity hypotheses is lacking. In this chapter, we review the limited existing research and theorise about the key differences between hunter-gatherer and industrialised societies that are likely to have profound implications for mental health. Specifically, we contrast the strong social support networks, egalitarianism, explorative modes of learning, sensitive child-rearing practices and present orientation of hunter-gatherers with corresponding features of industrialised populations. We argue that mismatches in these domains are partially responsible for of a vast array of mental illnesses, ranging from common mood disorders to behavioural pathologies and psychotic spectrum disorders. We hope that this chapter stimulates the generation and testing of mismatch hypotheses and, eventually, trials of interventions based on mismatch reduction. We end by offering suggestions for methodological approaches to this future research.