Esophageal cancer (EC) is mostly diagnosed due to clinical symptoms such as dysphagia or anemia. Depending on the staging and the histological subtype, squamous cell carcinoma or adenocarcinoma, patients with non-metastasized disease mostly undergo neoadjuvant chemoradiation or perioperative chemotherapy followed by esophageal resection. Nearly 50% of the curatively treated patients develop distant metastasis within 5 years, although no metastases were clinically evident at time of treatment. More recently, the concept of circulating tumor cells (CTC) has also been introduced for EC. CTC are thought to be the means of systemic tumor spread, with the ability to set up metastases in distant organs. Much effort has been made to capture, enrich and detect these very rare cells from the blood stream of EC patients. CTC have been found to be independent risk factors for worse prognosis in patients with EC. Pre- and intra-therapeutic CTC enrichment and detection has the potential to improve preoperative staging, and provide a differential indication for neoadjuvant therapeutic modality and an indication for adjuvant therapy.