The use of non-viral nanoparticulate systems for the delivery of therapeutic agents is receiving considerable attention for medical and pharmaceutical applications. This increasing interest results from the fact that these systems can be designed to meet specific physicochemical requirements, and they display low toxic and immunogenic effects. Among potential cellular targets by drug-loaded nanoparticles, macrophages are considered because they play a central role in inflammation and they act as reservoirs for microorganisms that are involved with deadly infectious diseases. The most common and potent drugs used in macrophage-mediated diseases treatment often induce unwanted side effects, when applied as a free form, due to the necessity of high doses to induce a satisfactory effect. This could result in their systemic spreading, a lack of bioavailability at the desired sites, and a short half-life. Therefore, the use of drug-loaded nanoparticles represents a good alternative to avoid, or at least decrease, side effects and increase efficacy. In this manuscript, we present an overview of the usefulness of nanoparticles for macrophage-mediated therapies in particular. We discuss, though not exhaustively, the potential of therapeutic agent-loaded nanoparticles for some macrophage-mediated diseases. We also underline the most important parameters that affect the interaction mechanisms of the macrophages and the physicochemical aspects of the particulate systems that may influence their performance in macrophage-targeted therapies.