A comprehensive map of molecular drug targets is presented, curating 893 human and pathogen-derived biomolecules through which 1,578 US FDA-approved drugs act. These include 667 human-genome-derived proteins targeted by drugs for human disease. Analysis shows the continued dominance of privileged target families across disease areas, along with the growth of novel first-in-class mechanisms, particularly in oncology. The study explores relationships between bioactivity class and clinical success, as well as orthologues between human and animal models and between pathogen and human genomes. Challenges in accurately defining drug targets are highlighted, along with conventions for deconvoluting molecular pharmacology and drug efficacy. The study emphasizes the importance of maintaining an accurate and up-to-date map of approved drugs and their efficacy targets. It discusses the complexities in defining efficacy targets, including the need for unambiguous evidence of therapeutic action through clear biomolecular partners. The study reassigned efficacy targets from primary literature and prescribing information, combining annotations from three independent teams. It also maps drugs to WHO ATC codes to obtain standard therapeutic indications. The study identifies 667 unique human protein efficacy targets and 189 pathogen protein efficacy targets. It examines how human protein targets distribute into homologous families, identifying privileged families such as GPCRs, ion channels, protein kinases, and nuclear hormone receptors. These families account for 44% of all human protein targets and are responsible for 70% of small-molecule drugs. The study also discusses the challenges in defining efficacy targets for oncology drugs, highlighting the growing number of kinase inhibitors and the need for accurate target assignments. It explores the relationship between drugs, target classes, and therapeutic areas, showing that certain target families are more prevalent in specific therapeutic areas. The study also addresses the challenges in defining efficacy targets for drugs with broad mechanistic effects, such as muscarinic receptor antagonists and broad-spectrum antibiotics. It discusses the importance of selecting appropriate model organisms for studying disease and validating novel target mechanisms. The study highlights the impact of large-scale systematic efforts on the identification of novel clinically validated targets, particularly in cancer. It discusses the relationship between drug mechanisms and bona fide cancer drivers, showing that many cancer drivers are newly discovered genes with little historical biological investigation. The study concludes that the current diversity of approved drugs and their targets reflects the continuous utility of protein families with druggable binding sites. It emphasizes the need for a reductionist approach to targeted therapy, incorporating drug combinations, network drugs, and polypharmacology, particularly in cancer and infectious disease. The study also highlights the importance of integrating pathological mechanisms of disease with diagnoses and therapeutics for successful drug discovery and application.A comprehensive map of molecular drug targets is presented, curating 893 human and pathogen-derived biomolecules through which 1,578 US FDA-approved drugs act. These include 667 human-genome-derived proteins targeted by drugs for human disease. Analysis shows the continued dominance of privileged target families across disease areas, along with the growth of novel first-in-class mechanisms, particularly in oncology. The study explores relationships between bioactivity class and clinical success, as well as orthologues between human and animal models and between pathogen and human genomes. Challenges in accurately defining drug targets are highlighted, along with conventions for deconvoluting molecular pharmacology and drug efficacy. The study emphasizes the importance of maintaining an accurate and up-to-date map of approved drugs and their efficacy targets. It discusses the complexities in defining efficacy targets, including the need for unambiguous evidence of therapeutic action through clear biomolecular partners. The study reassigned efficacy targets from primary literature and prescribing information, combining annotations from three independent teams. It also maps drugs to WHO ATC codes to obtain standard therapeutic indications. The study identifies 667 unique human protein efficacy targets and 189 pathogen protein efficacy targets. It examines how human protein targets distribute into homologous families, identifying privileged families such as GPCRs, ion channels, protein kinases, and nuclear hormone receptors. These families account for 44% of all human protein targets and are responsible for 70% of small-molecule drugs. The study also discusses the challenges in defining efficacy targets for oncology drugs, highlighting the growing number of kinase inhibitors and the need for accurate target assignments. It explores the relationship between drugs, target classes, and therapeutic areas, showing that certain target families are more prevalent in specific therapeutic areas. The study also addresses the challenges in defining efficacy targets for drugs with broad mechanistic effects, such as muscarinic receptor antagonists and broad-spectrum antibiotics. It discusses the importance of selecting appropriate model organisms for studying disease and validating novel target mechanisms. The study highlights the impact of large-scale systematic efforts on the identification of novel clinically validated targets, particularly in cancer. It discusses the relationship between drug mechanisms and bona fide cancer drivers, showing that many cancer drivers are newly discovered genes with little historical biological investigation. The study concludes that the current diversity of approved drugs and their targets reflects the continuous utility of protein families with druggable binding sites. It emphasizes the need for a reductionist approach to targeted therapy, incorporating drug combinations, network drugs, and polypharmacology, particularly in cancer and infectious disease. The study also highlights the importance of integrating pathological mechanisms of disease with diagnoses and therapeutics for successful drug discovery and application.