Summary: The macrophage lineage displays extreme functional and phenotypic heterogeneity, which appears to be because, in large part, of the ability of macrophages to functionally adapt to changes in their tissue microenvironment. This functional plasticity of macrophages plays a critical role in their ability to respond to tissue damage and/or infection and to contribute to clearance of damaged tissue and invading microorganisms, to recruitment of the adaptive immune system, and to resolution of the wound and of the immune response. Evidence has accumulated that environmental influences, such as stromal function and imbalances in hormones and cytokines, contribute significantly to the dysfunction of the adaptive immune system. The innate immune system also appears to be dysfunctional in aged animals and humans. In this review, the hypothesis is presented and discussed that the observed age-associated ‘dysfunction’ of macrophages is the result of their functional adaptation to the age-associated changes in tissue environments. The resultant loss of orchestration of the manifold functional capabilities of macrophages would undermine the efficacy of both the innate and adaptive immune systems. The macrophages appear to maintain functional plasticity during this dysregulation, making them a prime target of cytokine therapy that could enhance both innate and adaptive immune systems.