This chapter discusses the importance of natural antibiotics since most antibiotics used in clinical practice today are natural substances produced by microorganisms. These are often highly specific and highly effective against other microorganisms and higher organisms. The chemical-ecological role of antibiotic natural substances in microorganisms is explained by the strong competition for habitats. The history of the discovery of antibiotics, starting with the first plant extracts to the synthetic antibiotics of the modern era, is outlined. The structural diversity and effectiveness of antibiotic natural substances from microorganisms are highlighted, while plant sources have proven to be less promising. The role of antibiotics in medicine, their mechanisms, and their importance for public health are also discussed. In addition, important classes of antibiotics such as penicillins, cephalosporins, and polyketides, as well as their biosynthesis and biological effects, are thoroughly discussed. This chapter illuminates the chemical-ecological role of antibiotic natural substances in microorganisms and outlines the development history of antibiotics from the first plant extracts to the synthetic antibiotics of the modern era. The search for new antibiotics due to resistances and the challenges arising from the adaptability of microorganisms are discussed. This chapter provides a comprehensive overview of the importance of antibiotics in medicine and their role in combating infectious diseases.