Over the past four decades several studies have attempted to investigate the potential premorbid indicators of risk for schizophrenia. These studies have involved either long-term follow-up investigation of mostly unselected at risk subjects, or follow-back studies, and have examined behavioral/physiological indicators of variable significance. The “first generation” prospective studies have revealed some important clues to putative markers of risk for schizophrenia such as attentional and neuromotor abnormalities. However, these studies have often been criticized for their expense and lack of statistical power. Over the past decade an impressive wealth of data suggest developmentally mediated neurobiological alterations preceding clinical manifestations of schizophrenia and the critical importance of adolescence for emergence of such alterations. In this chapter, we discuss the merits and disadvantages of approaches to ascertain premorbid risk for schizophrenic illness, and argue that at the dawn of the twenty-first century, it is time to launch a new generation of high risk studies in schizophrenia. To be successful, such studies need to: (a) use hypothesis-driven and established neurobehavioral and biological markers that are guided by the emerging neurodevelopmental models of schizophrenia; (b) use an “enhanced” high risk strategy which defines risk by the presence of both genetic risk and biobehavioral or psychopathological risk; (c) address issues of diagnostic reliability, specificity, and generalizability; (d) develop a prospective follow-up design through the critical risk period closer to illness onset such as adolescence; and (e) use coordinated multicenter studies which are likely to enhance statistical power in such studies.