Over the last decade, progress in the management of metastatic colorectal cancer (CRC) has focused on the development of biologic therapy in addition to the back bone of combination chemotherapy. Anti-epidermal growth factor receptor (EGFR) antibodies and agents targeting angiogenesis are widely used in the clinic, and more recently, in a subset of patients with mismatch repair (MMR) deficient cancer, immunotherapy with immune check point inhibitors have been integrated into clinical practice. The major challenge with the use of these biologic therapies is determining predictive biomarkers to optimize patient selection. In this review, we discuss the most recent updates in the use of biologic therapy in CRC. We review data on the role of primary tumor location (PTL) (sidedness) as predictive biomarker and recent advances in treatment of CRC with BRAF mutation.