Methylation of nucleotides in rRNA is one of the basic mechanisms of bacterial resistance to protein synthesis inhibitors. The genes for corresponding methyltransferases have been found in producer strains and clinical isolates of pathogenic bacteria. In some cases, rRNA methylation by housekeeping enzymes is, on the contrary, required for the action of antibiotics. The effects of rRNA modifications associated with antibiotic efficacy may be cooperative or mutually exclusive. Evolutionary relationships between the systems of rRNA modification by housekeeping enzymes and antibiotic resistance-related methyltransferases are of particular interest. In this review, we discuss the above topics in detail.