Aflibercept (known as ziv-aflibercept in the USA and sold under the trade name Zaltrap®) is a human recombinant fusion protein with antiangiogenic effects that functions as a decoy receptor to bind vascular endothelial growth factors A and B and placental growth factor. Its unique mechanism of action with respect to other agents targeting angiogenesis led investigators to speculate that it may be more ubiquitously efficacious in tumors highly dependent on pathologic angiogenesis for their growth. Despite encouraging preclinical studies in various tumor types, aflibercept has not been proven efficacious in most later-phase clinical studies. In fact, its only currently held US Food and Drug Administration indication is in metastatic colorectal cancer in combination with 5-fluorouracil, leucovorin, and irinotecan for those patients previously treated with an oxaliplatin-containing chemotherapy regimen. Given aflibercept's toxicity profile and cost, further investigation is needed to better understand its mechanism of action and to discover predictive biomarkers for optimization of its appropriate use in treatment of cancer patients.