Simple SummaryColorectal cancer is the second most deadly tumor worldwide, despite the availability of screening plans and advanced treatment strategies. Molecular biomarkers predictive of prognosis have been identified, although there is currently limited knowledge of biomarkers predictive of the response to pharmacological treatment. In recent years, molecular classifications mainly able to predict colorectal cancer prognosis and recurrence risk have been proposed. The “consensus molecular subtype (CMS) classification” is the most known and has contributed to the understanding of genomic and epigenomic landscapes of colorectal cancer for better patient management. This classification categorizes colorectal cancer into four CMS categories (CMS1–4) that display different prognosis. This manuscript contextualized the CMS classification in different settings, discussing its relationships with precursor lesions, tumor immunophenotype, and gut microbiota, as well as its role in predicting prognosis and/or response to pharmacological treatments, as a crucial step towards precision medicine.AbstractColorectal cancer (CRC) is the second cause of cancer-related deaths in both sexes globally and presents different clinical outcomes that are described by a range of genomic and epigenomic alterations. Despite the advancements in CRC screening plans and treatment strategies, the prognosis of CRC is dismal. In the last two decades, molecular biomarkers predictive of prognosis have been identified in CRC, although biomarkers predictive of treatment response are only available for specific biological drugs used in stage IV CRC. Translational clinical trials mainly based on “omic” strategies allowed a better understanding of the biological heterogeneity of CRCs. These studies were able to classify CRCs into subtypes mainly related to prognosis, recurrence risk, and, to some extent, also to treatment response. Accordingly, the comprehensive molecular characterizations of CRCs, including The Cancer Genome Atlas (TCGA) and consensus molecular subtype (CMS) classifications, were presented to improve the comprehension of the genomic and epigenomic landscapes of CRCs for a better patient management. The CMS classification obtained by the CRC subtyping consortium categorizes CRC into four consensus molecular subtypes (CMS1–4) characterized by different prognoses. In this review, we discussed the CMS classification in different settings with a focus on its relationships with precursor lesions, tumor immunophenotype, and gut microbiota, as well as on its role in predicting prognosis and/or response to pharmacological treatments, as a crucial step towards precision medicine.