A marked paradigm shift in cancer therapy has occurred over the past 20 years. Systemic treatment has evolved from nonspecific cytotoxic chemotherapy to targeting cancer-associated pathways, profoundly changing treatment approaches in the metastatic and adjuvant settings. This review will highlight some of the major clinical advances in targeted cancer therapy in select epithelial malignancies made possible by the understanding of the molecular mechanisms driving tumor growth through genomic methods. J. Surg. Oncol. 2015 111:38–42. © 2014 Wiley Periodicals, Inc.