New drugs improved efficacy or convenience of treatment in metastatic colorectal cancer. The oral fluoropyrimidines capecitabine and UFT are less toxic but equally efficacious relative to intravenous bolus 5-fluorouracil (5-FU)/folinic acid (FA). These agents might be beneficial for patients who unlikely benefit from the more intensive combination therapy with infusional 5-FU/FA and irinotecan or oxaliplatin. First-line therapy with irinotecan or oxaliplatin and 5-FU/FA induces an objective response in up to 50% of the patients and may allow neoadjuvant concepts in unresectable liver metastasis. The combination therapy increased progression-free survival and in the case of irinotecan/5-FU/FA also overall survival when compared to 5-FU/FA. Sequential treatment with infusional 5-FU/FA plus oxaliplatin followed by 5-FU/FA plus irinotecan or vice versa results in a median survival exceeding 20 months. Thus, patients in a good performance status and with favorable prognostic parameters should be offered first-line combination treatment of irinotecan or oxaliplatin with 5-FU/FA, whereby 5-FU is preferably administered as an infusion for combination therapy. New targets in the treatment of colorectal cancer are the EGF and VEGF receptor. The monoclonal EGF receptor antibody cetuximab alone and in combination with irinotecan is active in second-line treatment. The VEGF antibody bevacizumab prolongs survival when given in combination with 5-FU/FA and irinotecan.