Schizophrenia is a complex epigenetic puzzle, the antecedents of which are presumed to lie in neurodevelopmental dysmaturation. This dysmaturation has an impact on children and adolescents at genetic risk for schizophrenia. In this framework, normative mechanisms of brain development that are highly dynamic in adolescence are likely to be disrupted in the at-risk adolescent brain. It is likely that what is affected is the integrity of brain networks that sub-serve fundamental domains of function such as sustained attention. Notably, expansion in proficiency in sustained attention that is characteristic of typical development is likely to be compromised in adolescents at risk for schizophrenia. This confluence of at-risk adolescents and neuro-behavioral domains of inquiry is discussed. We outline the evidence for developmental antecedents of schizophrenia, and their bases in systems and molecular mechanisms in the brain. Then we juxtapose these results against neuro-behavioral evidence of attention deficits in high-risk populations, and fMRI evidence of dysfunctional responses in critical brain regions. We end by advocating the application of systems-based approaches toward understanding the progression of network dysfunction in the adolescent risk-state.