Preclinical pharmacology and toxicology are essential elements of the drug discovery and development process and are critical in enabling the translation of findings from the laboratory and the clinic. The drug discovery process is complex and involves numerous iterative steps designed to optimize the pharmacological and drug-like properties of a candidate molecule, a New Chemical Entity (NCE), and minimize the potential for side effects and toxicities. Key concepts addressed in this record include: compound identification; lead optimization; pharmaceutical profiling; the use of animal models to predict efficacy and safety and toxicological assessment as these relate to the regulatory requirements for Phase I trial initiation. Commentary is also provided on the current challenges associated with translational medicine as it applies to the effective evolution of candidate NCEs into viable clinical candidates.