Novel antiangiogenic strategies with complementary mechanisms are needed to maximize efficacy and minimize resistance to current angiogenesis inhibitors. We explored the therapeutic potential and mechanisms of αPlGF, an antibody against placental growth factor (PlGF), a VEGF homolog, which regulates the angiogenic switch in disease, but not in health. αPlGF inhibited growth and metastasis of various tumors, including those resistant to VEGF(R) inhibitors (VEGF^RIs), and enhanced the efficacy of chemotherapy and VEGF^RIs. αPlGF inhibited angiogenesis, lymphangiogenesis, and tumor cell motility. Distinct from VEGF^RIs, αPlGF prevented infiltration of angiogenic macrophages and severe tumor hypoxia, and thus, did not switch on the angiogenic rescue program responsible for resistance to VEGF^RIs. Moreover, it did not cause or enhance VEGF^RI-related side effects. The efficacy and safety of αPlGF, its pleiotropic and complementary mechanism to VEGF^RIs, and the negligible induction of an angiogenic rescue program suggest that αPlGF may constitute a novel approach for cancer treatment.