There exists a tremendous opportunity in identifying and determining the appropriate predictive and prognostic biomarker(s) for risk stratification of patients with colorectal cancers (CRCs). Circulating tumor DNA (ctDNA) has emerged as a promising prognostic and possibly predictive biomarker in the personalized management of patients with CRCs. The disease is particularly suited to a liquid biopsy-based approach since there is a great deal of shedding of circulating tumor fragments (cells, DNA, methylation markers, etc). ctDNA has been shown to have several potential applications, including detecting minimal residual disease (MRD), monitoring for early recurrence, molecular profiling, and therapeutic response prediction. The utility of ctDNA has broadened from its initial use in the advanced/metastatic setting for molecular profiling and detection of acquired resistance mechanisms, toward identifying MRD, as well as early detection. Prospective studies such as CIRCULATE, COBRA, Dynamic II/III, and ACT3 are underway in the MRD setting to further understand how ctDNA may be used to inform clinical decision making using both tumor-informed and tumor-agnostic platforms. These prospective studies use ctDNA to guide management of patients with CRC and will be critical to help guide how and where ctDNA should or should not be used in clinical decision making. It is also important to understand that there are different types of ctDNA liquid biopsy platforms, each with advantages and disadvantages in different clinical indications. This review provides an overview of the current and evolving use of ctDNA in CRC.