The transition from nonclinical to First-in-Human (FIH) testing is one of the most challenging steps in drug development. In response to serious outcomes in a recent Phase 1 trial (sponsored by Bial), IQ Consortium/DruSafe member companies reviewed their nonclinical approach to progress small molecules safely to FIH trials. As a common practice, safety evaluation begins with target selection and continues through iterative in silico and in vitro screening to identify molecules with increased probability of acceptable in vivo safety profiles. High attrition routinely occurs during this phase. In vivo exploratory and pivotal FIH-enabling toxicity studies are then conducted to identify molecules with a favorable benefit-risk profile for humans. The recent serious incident has reemphasized the importance of nonclinical testing plans that are customized to the target, the molecule, and the intended clinical plan. Despite the challenges and inherent risks of transitioning from nonclinical to clinical testing, Phase 1 studies have a remarkably good safety record. Given the rapid scientific evolution of safety evaluation, testing paradigms and regulatory guidance must evolve with emerging science. The authors posit that the practices described herein, together with science-based risk assessment and management, support safe FIH trials while advancing development of important new medicines.