This presentation offers a comprehensive overview of the core principles and methodologies underlying lead optimization in medicinal chemistry. It details the systematic and iterative processes involved in refining lead compounds to attain optimal drug candidate profiles, with an emphasis on balancing efficacy, safety, pharmacokinetics, and physicochemical attributes. Through selected case studies, it addresses practical approaches to overcoming prevalent challenges such as enhancing potency, selectivity, and oral bioavailability, while also minimizing toxicity and stability concerns. The techniques and strategies presented are intended to serve as a resource for scientists dedicated to the innovation and development of new therapeutic agents.