Progress developing new and more effective treatments for psychiatric disorders, particularly depression and schizophrenia, has been stymied in part because of a lack of quantitative endpoints (biomarkers) to measure disease progression and response to therapy. Additional factors delaying the development of new drugs include a lack of mechanistic understanding of standard treatments and the complexity, and often long time course, of disease which makes disease modeling in laboratory animals challenging. Fortunately, developments along several fronts are providing new hope for a better understanding of disease progression and tractable mechanisms for drug discovery. The following topics will be explored in this symposium: progress in validating use of event-related potentials and other electrophysiological means to measure sensory deficits that are increasingly recognized as features of disease pathology; improved methods for brain imaging in patients to monitor illness progression and treatment effect; development of panels of blood biomarkers that reflect ongoing CNS disease pathology. Additionally, speakers will address strategies for "back-translating" findings in humans to animal models. Ultimately, combinations of approaches, reflecting a variety of specific endophenotypes, may pave the way toward a better understanding of disease and improved therapies.