Despite great progress in our understanding of the structure and functions of the CNS, the discovery of new drugs and their clinical development for many CNS disorders has been problematic. Recent studies have shown that reasons for high attrition rates for CNS drugs are due to two primary reasons: 1) failure in detecting clinical safety and 2) failure in late-stage nonclinical toxicology. Over half of the terminations are for safety liabilities most of which are in animals. While much advancement has been made in exploring in vitro and complementary systems in developmental neurotoxicity and acute neurotoxicity testing, these models is still not as widely applied in routine testing for CNS drugs. This symposium brings together experts in drug discovery and development across the globe to highlight case examples of CNS drug failures during late-stage preclinical toxicology/ first in human (FIH) trials, and sheds light on how some of these novel technologies can be used in lead candidate prioritization and early de-risking.