Growing evidence has demonstrated that circulating tumor DNA (ctDNA) detection in colorectal cancer might be a promising approach to address current important clinical questions. During chemotherapy for metastatic colorectal cancer, tumor cells acquire potential resistance by generating additional somatic mutations related to therapeutic resistance. ctDNA can capture the tumor landscape, including heterogeneity, which might provide the opportunity for additional treatment options. Moreover, ctDNA detection is advantageous, because it can monitor tumor heterogeneity serially, in a non-invasive manner. ctDNA is considered valid for detecting minimal residual disease after a curable resection. By utilizing ctDNA detection, adjuvant chemotherapy for patients with stage II-III colorectal cancer might be omitted for patients at low risk of recurrence; or conversely, adjuvant chemotherapy might be highly recommended for patients at high risk, based on ctDNA findings. During multidisciplinary treatments for locally advanced rectal cancer, it is essential to monitor the responses to sequential treatments to make appropriate decisions. Currently, these decisions are mainly based on radiological or pathological findings. ctDNA can add value by providing the real-time status of locally advanced rectal cancer. In this review, we summarized the current evidence and discussed future strategies for using ctDNA in the treatment of colorectal cancer.