In the past decade, significant advances have been made in the treatment of advanced colorectal cancer. Multiple cytotoxic agents and targeted therapies have been approved for management of metastatic colorectal cancer, leading to improvement of median overall survival in clinical trials to more than 30 months. Of note, before the introduction of biologics into treatment algorithms for metastatic colorectal cancer, median survival in phase III trials never exceeded 24 months. In 2016, the most common treatment approach in first line is a combination of chemotherapy with a biologic agent. The choice of therapy is influenced by patient factors (eg, age, comorbidities), tumor characteristics (eg, overall tumor burden, pattern of metastatic spread, mutation signature), potential adverse effects of therapy, and goals of treatment. The choice between irinotecan- or oxaliplatin-based cytotoxic chemotherapy regimen is primarily based on differential toxicity profile because they have similar efficacy. Currently, three biologic agents-bevacizumab, cetuximab, and panitumumab-are approved for first-line treatment of metastatic colorectal cancer. For patients with mutant RAS and likely mutant BRAF V600E tumors, bevacizumab is the only biologic agent that can be used in conjunction with cytotoxic chemotherapy. The choice of anti-epidermal growth factor antibody or anti-vascular endothelial growth factor antibody in RAS wild-type tumors is based on the specific clinical scenario. Recently, some clinical and molecular biomarkers have emerged that may help in decision making. In this review, we discuss the role of biologics in the management of first-line treatment of metastatic colorectal cancer.