Colorectal cancer is a commonly diagnosed disease accounting for significant morbidity and absorbing significant health resources globally. The underlying pathogenesis has long been known to occur due to acquired or hereditary genetic defects and genomic instability, which promotes a hypermutable genetic profile. Conventional diagnosis involves the acquisition of tumor tissue biopsies, which often involves invasive biopsy. This approach allows for in-depth pathomolecular analysis of tumor tissue, permitting clinicians to make individualized treatment plans based on disease stage and underlying molecular pathologies. Potential downsides of tissue biopsy include the inherent invasiveness (and therefore risk of local complications) and the inability to track changes in the genetic molecular landscape of the tumor microenvironment. Liquid biopsy offers a more reproducible and less invasive alternative to traditional tissue biopsy. Analysis of circulating tumor cells and circulating tumor DNA and RNA from bodily fluids could provide a sensitive method to supplement cancer screening, aid with prognostication, and provide predictive information to assist clinicians in determining suitable targeted treatment regimens for their patients. In this chapter, the current understanding of the molecular pathways involved in colorectal cancer and the potential clinical utility of the liquid biopsy in their management is discussed. This chapter also explores the nature of hereditary colon cancer and the role of liquid biopsy, particularly in the assessment of microsatellite instability.