Despite significant progress in understanding the biological systems and mechanisms involved in CNS disorders, use of this knowledge to realize practical gains in psychiatric care has been slow. To gain further insight into the reasons for failure and success in CNS drug discovery, preclinical predictors of success and failure for CNS drug discovery were evaluated for drugs developed for schizophrenia, depression, and anxiety. Specifically, we examined the success rate for drugs that had entered at least the later stages of preclinical research. Almost 500 compounds (140 antipsychotic; 211 antidepressant; 143 anxiolytic) were classified based on their molecular target(s) and evaluated based on preclinical validation, whether preclinical studies predicted clinical efficacy, and whether the compound displayed greater efficacy than 'conventional treatment' Results varied with indication but suggest that preclinical models have modest to good ability to predict overall clinical efficacy and adverse effect liability but are less able to predict efficacy greater than conventional treatment. In order to fully realize the potential therapeutic impact of recent basic science discoveries, it will be critical to increase attention on rigorous target validation at each step of the drug discovery process and focus efforts on developing new tools and clinical models that can be used for proof-of-concept studies in early clinical development. Also, increased attention should be focused on the development of early predictors of adverse effects of candidate compounds.