Netrin-1 is an embryonic, secreted, laminin-related glycoprotein that plays key roles in neuronal navigation, angiogenesis, and cell survival. It is primarily expressed during embryonic development but is also re-expressed by both cancer cells and the tumor microenvironment in a significant proportion of human neoplasms, including inflammation-associated colorectal cancer, metastatic breast cancer, lung cancer, neuroblastoma, lymphoma, and melanoma. Netrin-1 has been shown to stimulate epithelial-mesenchymal transition (EMT) in tumor cells. In the context of cancer, Netrin-1 has been implicated in tumor progression and resistance to chemotherapy. Targeting Netrin-1 with a monoclonal antibody (NP137) that blocks the Netrin-1–UNC5B interaction has shown promise in reducing tumor growth and EMT features in preclinical models and in patients with advanced solid tumors, including endometrial cancer. This targeting strategy not only reduces tumor cell numbers but also increases tumor sensitivity to chemotherapy by inhibiting EMT.