The increasing the colorectal cancer (CRC) prevalence and rate of metastasation stimulates the research efforts to identify potential targets for therapy, such as those found in tumor microenvironment (TME). TME consists both of cancer cells and cancer-associated cells of different types with their products, including tumor-associated macrophages (TAMs). The aim of our review is to present the literature available data regarding TAMs and their products, their interactions with different TME constituents in CRC development and progression, along with available therapies directed against TAMs. Our search was done in PubMed, Web of Science, and Google Scholar databases, using the following keywords “tumor associated-macrophages,” “tumor associated-cells,” “colorectal cancer,” and “tumor microenvironment.” According to available data, macrophages can adopt two distinct polarization states, by specific differentiation: proinflammatory or classically activated M1 macrophages and anti-inflammatory or alternatively activated M2 macrophages, with opposite involvement in cancer progression. The metastatic spread of CRC is based on the invasion-metastasis cascade, with multiple steps and the involvement of two significant mechanisms: epithelial-mesenchymal transition (EMT) and angiogenesis. TAMs are strongly involved in CRC development and progression, as M2 macrophages promote angiogenesis and immunosuppression. Considering TAMs complex roles, current therapies are tested in order to prevent monocyte infiltration, to repolarize macrophages phenotype, and to target them in metastatic CRC. As a consequence, multiple therapies have strong associations with TAMs and their re-education from M2 to M1 phenotype. Current studies may identify other TAMs targets for exploitation in future personalized therapies, such as TAMs products, TAMs metabolic substrates, and TME products involved in TAMs survival and function. The exploitation of TAMs attack and manipulation arsenal may be validated in future studies, while their efficiency might be tested in clinical application, contributing to CRC patients’ improved prognosis.