Bacteria have evolved various defense mechanisms against bacteriophage invasion, driven by a long-term evolutionary arms race. Among them, restriction-modification (R-M) systems, which protect bacteria by DNA restriction and modification, are prominent. R-M systems are categorized based on their DNA methylation mechanisms, restriction activities, and cofactor dependencies. Here, we review the molecular basis of R-M systems and the diverse strategies used by bacteriophages to evade these defenses. Furthermore, we highlight the co-evolutionary dynamics between R-M systems and phage countermeasures, providing insights into new approaches to combat bacterial resistance and pathogenicity. Beyond their defensive roles, the multifunctionality of R-M systems in broader biological and biotechnological contexts is also discussed.