Abstract: Concepts of mental disorder, and of the causal processes leading to disorder, have undergone radical changes over recent decades. Genetic findings, for example, have shown that (1) many conditions develop on the basis of a dimensional genetic liability; (2) the boundaries of some conditions extend much more broadly than indicated by the traditional diagnostic categories; and (3) there is substantial overlap between conditions previously thought to be distinctively different. On the other hand, genetic findings have also provided support for the validity of some diagnostic distinctions. Early molecular genetic research was conceptualized on the basis of the expectation that there would be disease-specific genes “for” schizophrenia, bipolar disorder, and the like. It has become apparent that, at best, this constitutes a misleading oversimplification. Almost all mental disorders (in childhood and adult life) have a multifactorial origin, and the genes are likely to operate through a range of direct and indirect routes. Gene-environment correlations and interactions are important, and there is a biological substrate for individual differences in responses to psychosocial stress and adversity, as well as for the effects of such stress and adversity on the organism. The empirical basis for these changes in concepts is reviewed, and the implications for clinical science and practice are considered.