Although the introduction of antibiotics in medicine has resulted in one of the most successful events and in a major breakthrough to reduce morbidity and mortality caused by infectious disease, response to these agents is not always predictable, leading to differences in their efficacy, and sometimes to the occurrence of adverse effects. Genetic variability, resulting in differences in the pharmacokinetics and pharmacodynamics of antibiotics, is often involved in the variable response, of particular importance are polymorphisms in genes encoding for drug metabolizing enzymes and membrane transporters. In addition, variations in the human leukocyte antigen (HLA) class I and class II genes have been associated with different immune mediated reactions induced by antibiotics. In recent years, the importance of pharmacogenetics in the personalization of therapies has been recognized in various clinical fields, although not clearly in the context of antibiotic therapy. In this review, we make an overview of antibiotic pharmacogenomics and of its potential role in optimizing drug therapy and reducing adverse reactions.