Our understanding of the diagnostic and prognostic use of circulating tumor DNA (ctDNA) in colorectal cancer (CRC) has broadly expanded over the past few years. The utilization of ctDNA to detect minimal residual disease is currently being employed across the continuum of cancer care. The lead-time of ctDNA positivity to radiographic recurrence in stage I to III CRC is up to 9 months on average, which provides a therapeutic window for a group of high-risk patients who will ultimately recur. There are several ongoing prospective clinical trials that investigate whether ctDNA can be used as an integral biomarker to risk stratify CRC patients and guide adjuvant treatment decisions. In this review, we summarize the evidence supporting the promise of ctDNA-defined MRD in CRC and highlight the current ctDNA guided adjuvant prospective clinical trials.