Tumor-associated macrophages (TAM) represent the major inflammatory component of the stroma of many tumors, able to affect different aspects of the neoplastic tissue. Many observations indicate that TAM express several M2-associated protumoral functions, including promotion of angiogenesis, matrix remodeling and suppression of adaptive immunity. The protumoral role of TAM in cancer is further supported by clinical studies that found a correlation between the high macrophage content of tumors and poor patient prognosis and by evidence showing that long-term use of non-steroidal anti-inflammatory drugs reduces the risk of several cancers. Here, we discuss evidence supporting the view that TAM represent a unique and distinct M2-skewed myeloid population and a potential target of anti-cancer therapy.