Since colorectal cancer is the second most prevalent cancer worldwide, its treatment remains a major challenge for researchers, gastroenterologists and oncologists. Despite curative resections, half of all patients diagnosed with colorectal cancer die because of their underlying disease. Integral chemotherapeutic components of standard regimens are 5-fluorouracil (5-FU), its modulation by folinic acid and irinotecan or oxaliplatin. All these drugs sequentially given have results in terms of median overall survival of more than 20 months in the palliative treatment of advanced colorectal cancer. Oral fluoropyrimidines, currently under clinical investigation, are likely to substitute continuous 5-FU. Inhibitors of growth factor receptors or their signaling may further prolong disease-free and overall survival rates. Preliminary evidence exists that improved adjuvant and neoadjuvant chemotherapy strategies may further improve the prognosis, mainly because more patients are able to go for primary or secondary surgery with curative intent.