Functionally polarized macrophages in chronic pathologies are highly adaptable cells displaying a functional response to tissue signals, which response can be reprogrammed to therapeutic advantage. The extent to which the functional heterogeneity of Mφs is dependent on the differentiation of functional sublineages remains unresolved. One alternative hypothesis proposes that Mφs are functionally plastic cells, which are capable of altering their functional activities progressively in response to progressively changing signaling molecules generated in their microenvironment. This “functional plasticity” hypothesis predicts that the functionally polarized Mφs in chronic pathologies do not represent Mφ sublineages but rather, are mutable phenotypes sustained by chronic signaling from the pathological environment. Solid TAMφs are chronically polarized to provide activities that support tumor growth and metastasis and suppress adaptive immune responses. In support of the functional plasticity hypothesis, administration of slow‐release microsphere‐encapsulated IL‐12 successfully reprogrammed TAMφs in situ, reducing Mφ support of tumor growth and metastasis and enhancing Mφ proimmunogenic activities. Increased knowledge of how Mφ function is regulated and how polarized Mφs can be reprogrammed in situ will increase our ability to control Mφ function in a variety of pathological states, including cancer and chronic inflammatory disease.