Oxaliplatin, irinotecan and 5-fluorouracil in combination with or without targeted therapies are well-documented treatment options for first- and second-line treatments of metastatic colorectal cancer. However, there are much less data on the beneficial effect on systemic therapy in the third-line setting. We therefore performed a systematic review of the current literature on third or later lines of treatment to patients with metastatic colorectal cancer after the use of approved drugs or combinations. A computer-based literature search was carried out using Pubmed and data reported at international meetings. Original studies reporting ≥15 patients who had previously received 5-fluorouracil, oxaliplatin and irinotecan were included. Furthermore, patients with KRAS wild type tumours should had received EGFR-directed therapy. Conventional chemotherapeutic agents as capecitabine, mitomycin C, and gemcitabine have limited or no activity. Retreatment with oxaliplatin might be an option in selected patients. In addition, rechallenge with EGFR-directed therapy might be a valuable strategy. Data also suggest that angiogenetic drugs may postpone further progression and prolong survival. Lately, regorafinib has been approved. In conclusion, our current knowledge is based on many retrospective studies, some phase II studies and very few randomized clinical trials. Further prospective phase III trials comparing an investigational drug or combination with best supportive care in third- or later lines of treatment in metastatic colorectal cancer are highly warranted. Identification of predictive biomarkers and improvement of our understanding of molecular mechanisms is crucial.