The tetracycline antibiotics, discovered in the 1940s, are a broad-spectrum class of antibiotics that inhibit protein synthesis by preventing the attachment of aminoacyl-tRNA to the ribosomal acceptor site. They are effective against a wide range of bacteria, including gram-positive and gram-negative species, as well as certain protozoan parasites. The favorable antimicrobial properties and lack of significant side effects have led to their extensive use in human and veterinary medicine. However, the emergence of microbial resistance has limited their effectiveness. This review covers the discovery and development of tetracyclines, their structure-activity relationships, mode of action, mechanisms of resistance, and the regulation of resistance gene expression. It also discusses the incidence of tetracycline resistance in pathogenic and commensal bacteria, the distribution of resistance genes, and the impact of resistance on the use of tetracyclines. The review highlights the emergence of resistance due to the acquisition of tet genes, the genetic and biochemical mechanisms of resistance, and the regulation of resistance gene expression. It also explores the development of new tetracyclines, such as the glycylcyclines, and strategies to enhance their effectiveness by inhibiting resistance mechanisms.The tetracycline antibiotics, discovered in the 1940s, are a broad-spectrum class of antibiotics that inhibit protein synthesis by preventing the attachment of aminoacyl-tRNA to the ribosomal acceptor site. They are effective against a wide range of bacteria, including gram-positive and gram-negative species, as well as certain protozoan parasites. The favorable antimicrobial properties and lack of significant side effects have led to their extensive use in human and veterinary medicine. However, the emergence of microbial resistance has limited their effectiveness. This review covers the discovery and development of tetracyclines, their structure-activity relationships, mode of action, mechanisms of resistance, and the regulation of resistance gene expression. It also discusses the incidence of tetracycline resistance in pathogenic and commensal bacteria, the distribution of resistance genes, and the impact of resistance on the use of tetracyclines. The review highlights the emergence of resistance due to the acquisition of tet genes, the genetic and biochemical mechanisms of resistance, and the regulation of resistance gene expression. It also explores the development of new tetracyclines, such as the glycylcyclines, and strategies to enhance their effectiveness by inhibiting resistance mechanisms.