This minireview discusses the mechanisms of erythromycin resistance, focusing on target site alteration in the 50S ribosomal subunit. Erythromycin inhibits protein synthesis by binding to the ribosome, and resistance often arises from posttranscriptional modifications of 23S rRNA, particularly the methylation of adenine at position A2058 by an N-methyltransferase specified by *erm* genes. Over 30 *erm* genes have been identified, with varying sequences and expression control elements. These genes confer resistance to macrolides, lincosamides, and streptogramin B antibiotics, collectively known as MLS resistance. The methylation of A2058 prevents the binding of these antibiotics to the ribosome, thereby conferring resistance. Other resistance mechanisms include altered ribosomal proteins, antibiotic modification, and altered antibiotic transport. The review also highlights the overlapping binding sites of MLS antibiotics on the ribosome and the functional interaction between these sites. Additionally, it discusses the role of ribosomal proteins and rRNA mutations in resistance, as well as the implications of posttranscriptional modifications for antibiotic resistance. The study of *erm* genes has provided insights into the molecular basis of resistance, and the identification of new *erm* genes continues to expand our understanding of this complex phenomenon. The review also addresses the clinical significance of these findings, particularly in the context of emerging resistant strains and the development of new antibiotics.This minireview discusses the mechanisms of erythromycin resistance, focusing on target site alteration in the 50S ribosomal subunit. Erythromycin inhibits protein synthesis by binding to the ribosome, and resistance often arises from posttranscriptional modifications of 23S rRNA, particularly the methylation of adenine at position A2058 by an N-methyltransferase specified by *erm* genes. Over 30 *erm* genes have been identified, with varying sequences and expression control elements. These genes confer resistance to macrolides, lincosamides, and streptogramin B antibiotics, collectively known as MLS resistance. The methylation of A2058 prevents the binding of these antibiotics to the ribosome, thereby conferring resistance. Other resistance mechanisms include altered ribosomal proteins, antibiotic modification, and altered antibiotic transport. The review also highlights the overlapping binding sites of MLS antibiotics on the ribosome and the functional interaction between these sites. Additionally, it discusses the role of ribosomal proteins and rRNA mutations in resistance, as well as the implications of posttranscriptional modifications for antibiotic resistance. The study of *erm* genes has provided insights into the molecular basis of resistance, and the identification of new *erm* genes continues to expand our understanding of this complex phenomenon. The review also addresses the clinical significance of these findings, particularly in the context of emerging resistant strains and the development of new antibiotics.