Commentary on the newly released European Society for Medical Oncology (ESMO) guidelines for the diagnosis and treatment of metastatic colorectal cancer (mCRC). After 6 years, individual chapters have been updated, from molecular tumor testing to diagnostic and treatment procedures to the implementation of newly registered medicinal products. The authors highlight the most important changes in the guidelines. Awareness of possible new treatments for mCRC is important to determine the treatment strategy for patients with mCRC. In this commentary, we focus primarily on the status of systemic treatment in unresectable disease.