In this 75th Anniversary issue commentary, we discuss a seminal review published in 2006 by Claire E. Lewis and Jeffrey W. Pollard in Cancer Research, entitled" Distinct Role of Macrophages in Different Tumor Microenvironments"(1). This was a milestone review for the journal that became very highly cited because of its incisive overview of important advances in learning how macrophages exert distinct effects on tumor pathophysiology based on their response to the specific microenvironment of tumors that they rove. This review also helped popularize the nomenclature of tumor-associated macrophages, or TAM, now a widely understood moniker used broadly in the field.