Antimicrobials are among the most prescribed drugs and their prescription increases with age, due to frailty and accrued risk factors for acquiring infections. Antimicrobial prescription in elderly patients must not only account for the risk of toxicity due to drug overexposure, but also of treatment failure or promotion of antimicrobial resistance due to under-dosage. This paper reviews the main antimicrobial, pharmacokinetic and pharmacodynamic variations induced by aging, comorbidities and polypharmacy, and how to take them into account to optimize antimicrobial prescription in elders.