Multiple lines of evidence have suggested that the in utero microenvironment is influenced by the maternal genotype and that such genetic differences can affect the prenatal development and long-term health of the offspring. This article reviews recent evidence for such effects on offspring mental health, with an emphasis on common neurodevelopmental disorders, such as attention deficit–hyperactivity disorder, autism and schizophrenia. We conclude that prenatal programming of offspring behavior has been found to be important both in humans and animal models and that this mechanism may explain some of the ‘missing heritability’ reported for genetic studies of complex disorders. Combining genetic and epidemiological research strategies, it is possible to disentangle the different effects of prenatal environmental and genetic exposures, which are particularly attractive candidates for primary prevention and early intervention strategies, for instance by correcting for metabolic deficiencies during critical weeks of prenatal development. Combined with advancing DNA sequencing and genotyping technologies, this knowledge may gradually transform our approach to psychiatric diagnostics, prevention and therapy.