First-line therapy for advanced colorectal cancer is rapidly moving from modulation and infusional administration of fluoropyrimidines in the past decades to more complex and more active regimens, with new chemotherapy drugs, oxaliplatin and irinotecan, and modulated targeted drugs inhibiting angiogenesis or the epidermal growth factor receptor (EGFR). The choice of first-line therapy is becoming more complex and is part of a global strategy also integrating individual prognostic factors, salvage surgery, and second-line therapy. Furthermore, we fear that limited financial resources will also influence the management of this disease.