Treatments of advanced colorectal cancer progressing after a 5FU based chemotherapy have not been extensively studied. However, 5FU in continuous infusion, L-OHP alone or in combination with 5FU and CPT11 have proved their efficacy in terms of tumor growth control and symptomatic effect. Irinotecan only has been evaluated prospectively in phase III studies. This paper reports the results of the two randomized European studies which have demonstrated the efficacy of irinotecan used at the dose of 350 mg/m2 administered over 90 minutes every 3 weeks in patients progressing after a 5FU-based chemotherapy. The first study compared irinotecan versus best supportive care in a group of 279 patients. It demonstrated an overall survival benefit (9.2 versus 6.5 months, p < 0.0001) with a one-year survival of 36.2% for patients treated by irinotecan versus 13.8%. There was also a quality of life benefit, especially for asthenia and pain in favor of the irinotecan arm. The second study compared irinotecan to a second-line infusional 5FU and randomized 260 patients. Irinotecan treated patients lived for significantly longer than those on 5FU: median time of survival was 10.8 months versus 8.5 months (p = 0.035). Survival at 1 year was increased from 32% in the 5FU arm to 45% in the irinotecan arm. Pain-free survival and symptom-free survival were better for patients treated by irinotecan and the global quality of life score was in favor of irinotecan when assigning null value to missing data due to death in both arms. Both treatments were equally well tolerated. These two randomized studies have proved the efficacy of irinotecan as second line chemotherapy for colorectal cancers progressing under 5FU. Combination of irinotecan to 5FU and/or L-OHP have now to be evaluated in this situation.