Colorectal cancer is one of the most frequent solid tumors in the Western world. Treatment options are dependent on the stage of the disease, the performance status of the patient, and increasingly the molecular makeup of the tumor. In countries with surveillance programs, the incidence rate as well as the mortality rate has gone down because of the earlier stages at which the tumors are detected. For rectal cancer, standard of care differs from that of colon cancer with regard to perioperative treatment. In the metastatic setting, treatment options are uniform for colorectal cancer. Over the years, treatment options have emerged from single-agent 5-fluorouracil (5-FU) treatment to combination regimens using 5-FU and oxaliplatin or irinotecan or both. Treatment efficacy in the metastatic setting has been increased with the introduction of targeted substances. These include (a) the anti-vascular endothelial growth factor-A (anti-VEGF-A) antibody bevacizumab, (b) the anti-epidermal growth factor receptor (anti-EGFR) antibodies cetuximab and panitumumab, (c) the anti-angiogenic multi-kinase inhibitor regorafenib, and (d) the anti-angiogenic compound aflibercept. Anti-EGFR antibodies have shown efficacy only in the subpopulations of tumors that do not have any mutation in KRAS and NRAS exon 2, 3, 4. Physicians have the choice in the first line to use anti-EGFR or anti-VEGF inhibitors in combination with chemotherapy based on treatment goals and patient performance. In recent years, tumor location has been shown to be prognostic and predictive for clinical outcome. Right-sided sporadic colon cancers differ significantly in molecular characteristics and, with the exception of microsatellite instability (MSI-H) tumors, are associated with poor prognosis. Tumors based on hereditary non-polyposis colorectal cancer, on the other hand, have excellent prognosis in stage II and III disease. Recent efforts have focused on the molecular classification of colorectal cancer with the purpose of establishing molecularly defined subgroups.