The treatment aims for advanced colorectal cancer (ACRC) patients are to prolong overall survival and to improve or maintain quality of life. Phase III studies published between 1997 and 2006 comparing different first or subsequent lines of treatment regimens were collected in order to evaluate the impact of these regimens on the overall survival and quality of life of ACRC patients. Our review shows that a first-line polychemotherapy regimen including oxaliplatin or irinotecan, in comparison with monochemotherapy, can improve overall survival. Second-line therapy and/or a cross-over between the first-line treatment arms can further modify the disease course. Hence, from the very beginning the treatment of ACRC patients must embrace a strategic approach taking into account all new agents available. Quality of life (QoL) was assessed in 52.3% of the first-line studies, while this was done in the whole group of studies evaluating pre-treated patients. QoL appears to be unrelated to the toxicity profile.