Management of patients with advanced colorectal cancer (A-CRC) is more rewarding because it achieves far better outcomes today than it did even 20 years ago in the era where supportive care and supportive care plus 5-FU chemotherapy was the best that we had to offer. With combination chemotherapy, the addition of targeted agents, and the judicious use of surgery to remove metastatic disease, median survival statistics have moved from 6 months then to 2-2.5 years now and some patients are rendered disease free for long intervals.  Initial therapy for advanced disease often includes two (FOLFOX, FOLFIRI) or even three (FOLFOXIRI) cytotoxic agents and an antiangiogenic agent (most often bevacizumab). There is evidence that optimal survival statistics are achieved when all available agents are delivered to patients with A-CRC across the course of their management. In the second line setting today only a small percentage of patients are appropriate for surgical resection. Most are being treated with palliative intent and the regimens available are in part determined by their experience in their first line of therapy. Balancing the activity and toxicity of regimens with the patient’s primary objectives requires developing an individualized treatment plan. Taking full advantage of all of the agents available and using them to maximum advantage is a challenge.  This session will explore current principles of advanced disease management including the use of genomic sequencing to influence the choice of standard and experimental therapies to maximize outcomes for the individuals in our clinics.