Simple SummaryHuman colorectal cancer (CRC) is a global health burden, most notably for minority populations. While screening tools have helped improve disease detection and surveillance, CRC is a complex disease with a diverse set of molecular features that are linked to the location of the primary tumor. These features provide challenges to treatment and improving patient outcome. In addition, tumor metastases to liver and other organ systems are a main cause of CRC-related mortality and represent a substantial obstacle to improving patient outcomes. In this review, we summarize CRC tumor subgroups, their molecular features, treatments and outcomes with attention to health disparities and tumor metastases.AbstractHuman colorectal cancer (CRC) is one of the most common malignancies in men and women across the globe, albeit CRC incidence and mortality shows a substantial racial and ethnic disparity, with the highest burden in African American patients. Even with effective screening tools such as colonoscopy and diagnostic detection assays, CRC remains a substantial health burden. In addition, primary tumors located in the proximal (right) or distal (left) sides of the colorectum have been shown to be unique tumor types that require unique treatment schema. Distal metastases in the liver and other organ systems are the major causes of mortality in CRC patients. Characterizing genomic, epigenomic, transcriptomic and proteomic (multi-omics) alterations has led to a better understanding of primary tumor biology, resulting in targeted therapeutic advancements. In this regard, molecular-based CRC subgroups have been developed that show correlations with patient outcomes. Molecular characterization of CRC metastases has highlighted similarities and differences between metastases and primary tumors; however, our understanding as to how to improve patient outcomes based on metastasis biology is lagging and remains a major obstacle to improving CRC patient outcomes. In this review, we will summarize the multi-omics features of primary CRC tumors and their metastases across racial and ethnic groups, the differences in proximal and distal tumor biology, molecular-based CRC subgroups, treatment strategies and challenges for improving patient outcomes.