Despite the advent of a considerable number of new antibiotics, treatment of intracellular pathogens still represents a major pharmaceutical challenge. The antibiotic concentration in those specialized niches are often subtherapeutic, for which high doses of antibiotics must often be used. This is not only costly but may also increase localized or systemic side effects. There is therefore an urgent need for materials and methods to enable clinicians to achieve therapeutically effective intracellular concentration of those antibiotics which show good efficiency in vitro. In this setting, the possible use of drug delivery systems (DDS) loaded with antibiotics that exhibit a high in vitro bactericidal activity deserves to be considered. Entrapping or encapsulating the drug within a delivery system provides a greater control of the pharmacokinetic behavior of the active molecule. This more efficient use of antibiotics may diminish their drawbacks and provide the basis for shortening the current time required by classical treatments. This review will focus on the role of DDS as a potential tool against intracellular bacteria.