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Ramucirumab, a human monoclonal antibody against vascular endothelial growth factor receptor 2 (VEGFR-2), is an antiangiogenic therapy that has been approved in combination with FOLFIRI in second-line treatment of metastatic colorectal cancer (mCRC), after progression on or after therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine. A thorough review of the safety of ramucirumab in this setting and in the context of other antiangiogenic agents is merited. Areas covered: We provide an overview of activity and summarize in detail the overall safety and tolerability profile of ramucirumab in mCRC patients on the basis of a literature review of all published clinical trials in this setting, including both single-agent and combination studies. A focus on adverse events of interest and specific populations is included, as well as a critical comparison with other antiangiogenic therapies. Expert opinion: As an effective agent in pretreated mCRC patients, the toxicity profile of ramucirumab is similar to those of other angiogenesis inhibitors used in the second-line mCRC setting. The next challenge will be to find biomarkers of response and toxicity to antiangiogenic therapies in order to more effectively implement personalized medicine in these patients.