Neuropsychiatry stands to benefit enormously from the new research framework afforded by the sequencing of the human genome and from examining the role of molecular genetics on the clinical presentation of psychiatric patients. A solid foundation is essential if novel genetic breakthroughs are to be translated to successful clinical agents. However, this new research program is magnitudes more complex than any enterprise embarked on hitherto and requires the development, validation and deployment of novel behavioural and neurophysiological phenotypes in order to unravel the pathologies within neural functional systems. This Special Issue provides an introduction to some important findings and implications for neuropsychiatry. The role of specific functional polymorphisms - including genomic mutations - as well as ‘generalist’ genes are explored in childhood, adolescence and adulthood in terms of their modulatory roles on variables present at the level of clinical diagnosis as well as those evident at the level of intermediate neurocognitive and neurophysiological phenotypes, such as emotional reactivity, working memory, executive function, episodic memory and general intelligence. Methodological considerations of this research enterprise are discussed, such as genome wide association studies, the role of cognitive ontologies for neuropsychiatric phenomics as well as possible novel cognitive endophenotypes.