In the absence of sufficient clinical data to directly compare and determine the superiority of any angiogenesis inhibitor for different patient subpopulations in different disease settings, oncologists find it difficult to make complex decisions in selecting the optimal treatment regimen for their patients with metastatic colorectal cancer (mCRC). Intense research in recent years has yielded substantial advances in our understanding of the biology of tumors of the colon and rectum, resulting in the identification of essential biologic targets within the tumors and their microenvironment and incorporation of efficacious targeted agents into traditional treatment algorithms for mCRC. Targeted agents directed against the vascular endothelial growth factor (VEGF) pathway have gained prominence in the past decade; several angiogenesis inhibitors, such as the anti-VEGF monoclonal antibody bevacizumab, the soluble VEGF decoy receptor aflibercept, and the multikinase inhibitor regorafenib that targets tyrosine kinase receptors including the VEGF receptor (VEGFR), are approved as single agents or in combination with chemotherapy for patients with newly diagnosed and recurrent disease. 1-6 Ramucirumab, a monoclonal antibody targeting the VEGFR2, has also been shown to improve outcomes in mCRC patients in combination with chemotherapy. 7 These agents have different mechanisms of action for targeting the VEGF/VEGFR pathway and have demonstrated effectiveness in various subsets of patients with mCRC in phase III trials. In unresectable mCRC, the standard of care for initial treatment is chemotherapy (FOLFOX [folinic acid, 5-fluorouracil (5-FU), and oxaliplatin] or FOLFIRI [folinic acid, 5-FU, and irinotecan]) with bevacizumab. Despite the efficacy of the regimen, benefits are short-lived and disease in patients invariably progresses. 8 Based on the results of the treatment through multiple lines (TML) study (also referred to as ML18147), bevacizumab in combination with second-line chemotherapy is approved for treatment beyond disease progression in mCRC patients who receive a first-line chemotherapy or bevacizumab regimen. 3 In addition, multiple second-generation angiogenesis inhibitors have been investigated in the setting after disease progression to improve on the clinical outcomes with bevacizumab. Aflibercept is approved in combination with FOLFIRI for mCRC patients that are resistant to or have disease progression after an oxaliplatin-containing regimen. Benefit with aflibercept has been noted regardless of previous bevacizumab use. 4 Regorafenib has been investigated as a single agent and is approved in patients with mCRC who have previously received therapy with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, with an anti-VEGF therapy, and, if Kirsten rat sarcoma viral oncogene homolog (KRAS) wild type, with an anti-endothelial growth factor receptor therapy. Moreover, a phase III study that combined ramucirumab, a novel antiVEGFR2 monoclonal antibody, with FOLFIRI has reported to improvement of the outcome in patients with recurrence previously treated with chemotherapy with bevacizumab. 7 As yet, there are no prospective, direct comparisons between currently approved and emerging angiogenesis inhibitors in combination with standard chemotherapy in first- or second-line settings for mCRC. Health care professionals who manage patients with mCRC are faced with many challenges as they seek to develop optimal personalized treatment plans for their patients through multiple lines of therapy. Thus, clinicians who care for patients with mCRC need to able to evaluate the latest clinical trial data and critically interpret their results, including comparison of various selection and eligibility criteria for different angiogenesis inhibitors. In the era of targeted therapeutics for personalized care, expert recommendations are needed for the appropriate selection of efficacious new targeted regimens based on patient characteristics and eligibility, and optimal sequencing and combination of agents across multiple lines of therapy to maximize clinical benefit.