This chapter reviews the several approaches to investigate premorbid risk for schizophrenia. It presents a critical appraisal of the existing studies focusing on the populations at risk for schizophrenia, the issues surrounding study design, predictive and outcome factors identified so far, and the timing of the studies. Studies of premorbid risk, risk for schizophrenia and prospective studies have utilized genetic propensity, neurobehavioral markers, or psychopathology to identify the risk status. The chapter outlines the potential merits and disadvantages of these strategies, reviews the lessons learned from the early first high-risk (HR) studies and presents a rationale for more focused next-generation studies to examine premorbid risk. Recent advances in developmental neurobiology and neuroscience make it reasonable to expect a paradigm shift in research on schizophrenia. It is hoped that the third millennium will usher in a new generation of research studies on high-risk (HR) populations.