Colorectal cancer is a leading cause of cancer death worldwide. Recently the results of a number of well-designed clinical trials conducted across the world have led to important advances in the management of advanced colorectal cancer. These iterative studies fostered the evolution from a standard single-agent approach using fluorouracil (5-FU) to new combination regimens including capecitabine, irinotecan, and oxaliplatin in addition to 5-FU. These developments have significantly expanded the expectations of oncologists managing the disease and the options available to individuals, leading to a likelihood of extended survival compared to previous statistics. The identification of new combination chemotherapy regimens and the integration of novel targeted therapies with cytotoxic chemotherapies are areas of active clinical investigation. In this paper selected phase III studies from around the globe that tested these new chemotherapy options and led to new standards of care and better expectations for patients with advanced colorectal cancer are reviewed.