Microbial drug discovery has significantly contributed to global health, with secondary metabolites from microbes accounting for half of today's pharmaceuticals. This review highlights the 80-year journey of microbial drug discovery, starting with penicillin's discovery in 1928. Microbes produce a wide range of bioactive compounds, including antibiotics, antifungals, and antivirals, which have been crucial in treating diseases. Natural products, derived from primary or secondary metabolism, have led to the discovery of over a million compounds, with 50-60% from plants and 5% from microbes. Many chemically synthesized drugs originate from natural sources, such as aspirin from willow bark. Microbial secondary metabolites have been vital in combating infectious diseases, increasing life expectancy, and developing new antibiotics. However, the rise of antibiotic resistance and multidrug resistance has necessitated the development of new antimicrobial agents. The emergence of new diseases and the need for novel anti-infective compounds have driven research into microbial-derived drugs. Additionally, the development of new antibiotics is also driven by their toxicity and the need to treat resistant bacteria. The discovery of new antimicrobial agents, such as teicoplanin, pristinamycin, and daptomycin, has been crucial in addressing resistance. Antifungal agents, such as echinocandins and posaconazole, have also been developed to combat fungal infections. Microbial metabolites have also been used in antitumor drugs, enzyme inhibitors, and immunosuppressants, highlighting their diverse applications in medicine. The ongoing challenge of antibiotic resistance and the need for new drugs continue to drive research in microbial drug discovery.Microbial drug discovery has significantly contributed to global health, with secondary metabolites from microbes accounting for half of today's pharmaceuticals. This review highlights the 80-year journey of microbial drug discovery, starting with penicillin's discovery in 1928. Microbes produce a wide range of bioactive compounds, including antibiotics, antifungals, and antivirals, which have been crucial in treating diseases. Natural products, derived from primary or secondary metabolism, have led to the discovery of over a million compounds, with 50-60% from plants and 5% from microbes. Many chemically synthesized drugs originate from natural sources, such as aspirin from willow bark. Microbial secondary metabolites have been vital in combating infectious diseases, increasing life expectancy, and developing new antibiotics. However, the rise of antibiotic resistance and multidrug resistance has necessitated the development of new antimicrobial agents. The emergence of new diseases and the need for novel anti-infective compounds have driven research into microbial-derived drugs. Additionally, the development of new antibiotics is also driven by their toxicity and the need to treat resistant bacteria. The discovery of new antimicrobial agents, such as teicoplanin, pristinamycin, and daptomycin, has been crucial in addressing resistance. Antifungal agents, such as echinocandins and posaconazole, have also been developed to combat fungal infections. Microbial metabolites have also been used in antitumor drugs, enzyme inhibitors, and immunosuppressants, highlighting their diverse applications in medicine. The ongoing challenge of antibiotic resistance and the need for new drugs continue to drive research in microbial drug discovery.