Recent studies have shown that macrophages play an important part in both tumor initiation and various key steps in growth and metastasis. These cells show a remarkable degree of plasticity during tumor development with a “switch” in macrophage phenotypes occurring during the course of tumor progression. During chronic inflammation they appear to predispose a given tissue to tumor initiation by the release of factors that promote neoplastic transformation. Following this, their phenotype shifts more toward one that is immunosuppressive and supports tumor growth, angiogenesis, and metastasis. In this review, we discuss the evidence for this plasticity of macrophage functions, the specific signaling mechanisms that may be regulating it, and the new targets for anticancer therapies highlighted by these findings.