This podcast offers a comprehensive overview of combination drug therapy, a strategy crucial for treating complex diseases by simultaneously targeting multiple pathways. It examines the current landscape across various therapeutic domains, noting the established use in infectious diseases, rapid expansion in oncology, nascent efforts in neurodegenerative disorders, and cautious application in immunology. We examine whether the discovery of new therapeutic combinations is accelerating, highlighting a significant surge in oncology, particularly with immunotherapy combinations. A critical discussion is presented on synergy versus additivity, revealing that most successful combinations primarily achieve their benefits through additive or independent drug actions rather than profound synergistic effects. Furthermore, the source highlights significant challenges related to increased toxicity and substantial costs associated with combination regimens, which often exceed traditional cost-effectiveness thresholds. Finally, it explores regulatory and ethical considerations, highlighting FDA guidance for co-development and IND exemptions, and details how Artificial Intelligence (AI) and machine learning are poised to revolutionize combination therapy design, from predicting synergistic pairs and aiding patient stratification to identifying low cross-resistance partners, while acknowledging current data and validation bottlenecks in translating AI predictions to clinical practice. Produced by Dr. Jake Chen.