The article discusses the origin, diffusion, and evolution of CTX-M β-lactamases, a significant group of enzymes that confer resistance to β-lactam antibiotics. The CTX-M enzymes are derived from chromosomal $bla_{CTX-M}$ genes of Kluyvera species, which have been mobilized into mobile genetic elements such as insertion sequences (ISEs) and transposons. In silico analyses indicate at least nine independent mobilization events, resulting in different CTX-M clusters. The capture of these genes by highly mobilizable structures and the selective pressure of β-lactam antibiotics have driven the diversification of CTX-M enzymes. The article also highlights the global spread of CTX-M-producing organisms, often associated with multi-drug resistant and virulent clones, and the emergence of new variants, including those not inhibited by β-lactamase inhibitors. The genetic environments surrounding $bla_{CTX-M}$ genes, including plasmids and transposons, play a crucial role in their mobilization, spread, and maintenance. The article concludes by discussing the potential routes of dissemination, such as international travel and immigration, and the presence of CTX-M enzymes in various environments, including food and animals.The article discusses the origin, diffusion, and evolution of CTX-M β-lactamases, a significant group of enzymes that confer resistance to β-lactam antibiotics. The CTX-M enzymes are derived from chromosomal $bla_{CTX-M}$ genes of Kluyvera species, which have been mobilized into mobile genetic elements such as insertion sequences (ISEs) and transposons. In silico analyses indicate at least nine independent mobilization events, resulting in different CTX-M clusters. The capture of these genes by highly mobilizable structures and the selective pressure of β-lactam antibiotics have driven the diversification of CTX-M enzymes. The article also highlights the global spread of CTX-M-producing organisms, often associated with multi-drug resistant and virulent clones, and the emergence of new variants, including those not inhibited by β-lactamase inhibitors. The genetic environments surrounding $bla_{CTX-M}$ genes, including plasmids and transposons, play a crucial role in their mobilization, spread, and maintenance. The article concludes by discussing the potential routes of dissemination, such as international travel and immigration, and the presence of CTX-M enzymes in various environments, including food and animals.