We now know that a single human gene mutation may present with any of multiple phenotypes, and vice versa, that a range of genetic abnormalities may cause a single disease phenotype. These observations lead to the conclusion that a deeper understanding is needed of the way changes at one spatial or temporal level of brain organisation integrate and translate into others, eventually resulting in behaviour and cognition or their abnormalities. The traditional approach to determining disease nosology - eliciting symptoms and signs, creating clusters of like individuals and defining diseases primarily on those criteria has not generated fundamental breakthroughs in understanding sequences of pathophysiological mechanisms that produce the repertoire of psychiatric and neurological diseases. It is time to radically overhaul our epistemological approach to such problems. We now know a great deal about brain structure and function. From genes, through functional protein expression the mechanisms are known in some detail. When it comes to cerebral microcircuits, to networks and to functionally specialised areas defined by physiological cell recording, microanatomy and human neuroimaging we have accumulated a mass of knowledge about the brain that so far defies easy integration and hence interpretation. Europe’s Human Brain Project proposes a medical informatics platform that capitalises on modern advances in information technology, from supercomputers to distributed and interactive databases, allied to new mathematics and statistics, to federate and integrate existing and future clinical and neuroscientific data for a more biologically based, mechanistic approach to brain disorders. The implications for drug discovery range from more accurate, biologically supported diagnostics, new ways of identifying treatment targets, a priori profiling of primary and secondary effects of potential therapies in silico, a rethink about drug trial methodology and a route towards precision and personalised medicine.