The activation of immune cells in response to stimuli present in their microenvironment is regulated by their metabolic profile. Unlike the signal transduction events, which overlap to a huge degree in diverse cellular processes, the metabolome of a cell reflects a more precise picture of cell physiology and function. Different factors governing the cellular metabolome include receptor signaling, macro and micronutrients, normoxic and hypoxic conditions, energy needs, and biomass demand. Macrophages have enormous plasticity and can perform diverse functions depending upon their phenotypic state. This review presents recent updates on the cellular metabolome and molecular patterns associated with M1 and M2 macrophages, also termed “classically activated macrophages” and “alternatively activated macrophages,” respectively. M1 macrophages are proinflammatory in nature and predominantly Th1‐specific immune responses induce their polarization. On the contrary, M2 macrophages are anti‐inflammatory in nature and primarily participate in Th2‐specific responses. Interestingly, the same macrophage cell can adapt to the M1 or M2 phenotype depending upon the clues from its microenvironment. We elaborate on the various tissue niche‐specific factors, which govern macrophage metabolism and heterogeneity. Furthermore, the current review provides an in‐depth account of deregulated macrophage metabolism associated with pathological disorders such as cancer, obesity, and atherosclerosis. We further highlight significant differences in various metabolic pathways governing the cellular bioenergetics and their impact on macrophage effector functions and associated disorders.

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