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Macrolides bind the bacterial 50S ribosomal subunit at 23S rRNA and block translocation, inhibiting protein synthesis. They are generally bacteriostatic, though they may be bactericidal against highly susceptible Gram-positive organisms at high concentrations. Their spectrum includes Gram-positive cocci and atypical pathogens such as Mycoplasma, Chlamydia, and Legionella, with limited activity against Enterobacteriaceae. Clinical applications include respiratory infections, pertussis, chlamydial infections, and selected uses such as clarithromycin-containing H. pylori therapy and fidaxomicin for C. difficile colitis. Key safety considerations include gastrointestinal effects, QT prolongation, and drug interactions: erythromycin and clarithromycin strongly inhibit CYP3A4, whereas azithromycin does not significantly do so. Resistance mechanisms can produce cross-resistance among macrolides and related antibiotics.