This review article, authored by Arnold L. Demain and Sergio Sanchez, highlights the significant contributions of microorganisms to human health and well-being through the production of primary and secondary metabolites. The discovery of penicillin by Alexander Fleming in 1928 marked the beginning of microbial drug discovery, leading to the isolation and development of numerous antibiotics and other pharmaceuticals. The article discusses the historical context of fermentation techniques, which have been used for thousands of years, and the increasing role of microorganisms in the production of antibiotics and other drugs. The review emphasizes the importance of natural products in drug discovery, noting that about 50-60% of the best-selling pharmaceuticals in 1991 were either natural products or their derivatives. It also highlights the challenges posed by antibiotic resistance, particularly in Gram-negative bacteria, and the need for new antibiotics to combat these resistant strains. The article provides examples of chemically synthesized drugs derived from natural sources, such as acyclovir and cytarabine, and discusses the development of novel antimicrobial agents to address the growing problem of antibiotic resistance. Additionally, the review covers the broader applications of microbial metabolites beyond antibacterial, antifungal, and antiviral infections, including immunosuppressants, antitumor drugs, enzyme inhibitors, and hypocholesterolemic drugs. It details the discovery and clinical use of various microbial metabolites, such as actinomycin D, anthracyclines, bleomycin, mitosanes, mithramycin, streptozotocin, pentostatin, calicheamicins, taxol, epothilones, cyclosporin A, sirolimus, and tacrolimus. Overall, the article underscores the ongoing importance of microbial drug discovery in addressing global health challenges and the need for continued research to develop new antimicrobial agents and manage antibiotic resistance.This review article, authored by Arnold L. Demain and Sergio Sanchez, highlights the significant contributions of microorganisms to human health and well-being through the production of primary and secondary metabolites. The discovery of penicillin by Alexander Fleming in 1928 marked the beginning of microbial drug discovery, leading to the isolation and development of numerous antibiotics and other pharmaceuticals. The article discusses the historical context of fermentation techniques, which have been used for thousands of years, and the increasing role of microorganisms in the production of antibiotics and other drugs. The review emphasizes the importance of natural products in drug discovery, noting that about 50-60% of the best-selling pharmaceuticals in 1991 were either natural products or their derivatives. It also highlights the challenges posed by antibiotic resistance, particularly in Gram-negative bacteria, and the need for new antibiotics to combat these resistant strains. The article provides examples of chemically synthesized drugs derived from natural sources, such as acyclovir and cytarabine, and discusses the development of novel antimicrobial agents to address the growing problem of antibiotic resistance. Additionally, the review covers the broader applications of microbial metabolites beyond antibacterial, antifungal, and antiviral infections, including immunosuppressants, antitumor drugs, enzyme inhibitors, and hypocholesterolemic drugs. It details the discovery and clinical use of various microbial metabolites, such as actinomycin D, anthracyclines, bleomycin, mitosanes, mithramycin, streptozotocin, pentostatin, calicheamicins, taxol, epothilones, cyclosporin A, sirolimus, and tacrolimus. Overall, the article underscores the ongoing importance of microbial drug discovery in addressing global health challenges and the need for continued research to develop new antimicrobial agents and manage antibiotic resistance.