Macrophages are professional phagocytes that play key roles in immune surveillance and host defense against a variety of external stimuli, including engineered nanomaterials (ENMs). Physicochemical characteristics of ENMs such as size, shape, and surface charge are factors that determine macrophage recognition and uptake through various endocytotic mechanisms. Moreover, toll-like receptors (TLRs) and scavenger receptors (SRs) on the surface of macrophages facilitate binding, uptake, and intracellular signaling in response to specific types of ENMs. Biocorona formation further modulates the interaction of ENMs with cell-surface receptors. The immune response of macrophages to ENMs, including inflammasome activation and alternative polarization, plays important roles in immune-mediated diseases such as fibrosis, asthma, and cancer.