This chapter, expanding on the foundational knowledge, offers an extensive review of the computational methods used to predict and study the metabolism of lead compounds. The importance of this knowledge extends beyond academic interest; it is a critical component of drug discovery that affects the efficacy, safety, and clinical success of new therapeutic agents. As the field advances, novel computational models continue to emerge, promising to enhance the predictability and efficiency of drug development processes. By addressing these advanced topics and forecasting future trends, this chapter equips students and researchers with the necessary tools to navigate the evolving landscape of drug metabolism. Through a balanced integration of current research, expert insights, and practical applications, this chapter underscores the significance of metabolism studies in the broader context of drug discovery and development, highlighting its crucial role in shaping the next generation of pharmaceuticals. This chapter explores the processes and methodologies essential for predicting metabolism in lead molecules—a crucial aspect of the pharmacokinetic profiling of new chemical entities in drug discovery. Early on, it is vital to define that ‘drug metabolism’, synonymous with ‘drug biotransformation’, refers to the chemical modifications that drugs undergo within the body to facilitate their elimination. These modifications can significantly influence the drug’s efficacy, safety, and overall therapeutic profile. ‘Lead molecules’ are potent compounds identified during the initial stages of drug discovery that exhibit promising activity against a biological target but may require optimisation before progressing to clinical trials. Understanding the metabolism of these molecules is paramount, as it determines their fate in the body and their potential to become safe and effective drugs.