The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for Colon Cancer focus on the use of systemic therapy for metastatic disease. The guidelines consider various monotherapies and combination regimens, including 32 different treatments across up to 7 lines of therapy. Treatment selection is based on factors such as treatment history, disease extent, patient goals, efficacy and toxicity profiles, KRAS/NRAS mutational status, and patient comorbidities and preferences. The location of the primary tumor, BRAF mutation status, and tumor microsatellite stability are also considered in treatment decisions. The guidelines recommend specific regimens for initial therapy, including FOLFOX, FOLFIRI, CapeOx, infusional 5-FU/LV or capecitabine, and FOLFOXIRI. For subsequent therapy, options include irinotecan, oxaliplatin, capecitabine, bevacizumab, cetuximab, panitumumab, ziv-aflibercept, ramucirumab, regorafenib, trifluridine-tipiracil, pembrolizumab, and nivolumab. The choice of therapy is guided by the goals of treatment, prior therapies received, tumor mutational profile, and toxicity profiles of the drugs. The guidelines emphasize the importance of KRAS/NRAS genotyping for all patients with metastatic CRC to guide treatment decisions. Patients with known KRAS or NRAS mutations should not be treated with cetuximab or panitumumab, as these mutations indicate a lack of response to EGFR inhibitors. BRAF V600E mutations are also predictive of poor response to EGFR inhibitors, and BRAF genotyping is recommended at diagnosis of stage IV disease. The guidelines also discuss the role of HER2 overexpression, which is rare in CRC but more common in RAS/BRAF wild-type tumors. While HER2 overexpression does not have a proven prognostic role, it may be predictive of resistance to EGFR-targeting monoclonal antibodies. Overall, the NCCN guidelines aim to provide a comprehensive framework for the management of metastatic colon cancer, emphasizing the importance of individualized treatment decisions based on patient-specific factors and the latest evidence.The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for Colon Cancer focus on the use of systemic therapy for metastatic disease. The guidelines consider various monotherapies and combination regimens, including 32 different treatments across up to 7 lines of therapy. Treatment selection is based on factors such as treatment history, disease extent, patient goals, efficacy and toxicity profiles, KRAS/NRAS mutational status, and patient comorbidities and preferences. The location of the primary tumor, BRAF mutation status, and tumor microsatellite stability are also considered in treatment decisions. The guidelines recommend specific regimens for initial therapy, including FOLFOX, FOLFIRI, CapeOx, infusional 5-FU/LV or capecitabine, and FOLFOXIRI. For subsequent therapy, options include irinotecan, oxaliplatin, capecitabine, bevacizumab, cetuximab, panitumumab, ziv-aflibercept, ramucirumab, regorafenib, trifluridine-tipiracil, pembrolizumab, and nivolumab. The choice of therapy is guided by the goals of treatment, prior therapies received, tumor mutational profile, and toxicity profiles of the drugs. The guidelines emphasize the importance of KRAS/NRAS genotyping for all patients with metastatic CRC to guide treatment decisions. Patients with known KRAS or NRAS mutations should not be treated with cetuximab or panitumumab, as these mutations indicate a lack of response to EGFR inhibitors. BRAF V600E mutations are also predictive of poor response to EGFR inhibitors, and BRAF genotyping is recommended at diagnosis of stage IV disease. The guidelines also discuss the role of HER2 overexpression, which is rare in CRC but more common in RAS/BRAF wild-type tumors. While HER2 overexpression does not have a proven prognostic role, it may be predictive of resistance to EGFR-targeting monoclonal antibodies. Overall, the NCCN guidelines aim to provide a comprehensive framework for the management of metastatic colon cancer, emphasizing the importance of individualized treatment decisions based on patient-specific factors and the latest evidence.