Endoscopic cryotherapy (Cryo) or local application of cryogen to the gastrointestinal mucosa is a thermal ablative treatment that has been used for Barrett’s esophagus (BE) and high grade dysplasia, as well as for palliative use in esophageal adenocarcinoma (EAC). Most of the existing data are related to this indication, but endoscopic cryotherapy has also successfully used for treatment of gastric antral vascular ectasia and radiation proctitis. Cryo using liquid nitrogen or compressed carbon dioxide or nitrogen gas is delivered via an endoscopic spray catheter resulting in tissue destruction without direct contact. Freezing occurs due to the Joules-Thompson effect. Data on the optimal dosimetry are limited, but a variable number of cycles of 8–20 s of freeze and thaw have been used. For Barrett’s esophagus, there are no randomized controlled trials. However, retrospective studies on the use of Cryo in patients with high grade dysplasia and/or early adenocarcinoma suggest great potential safety and efficacy for curative intent. Complete response rates of 68–100% have been reported. Complete response rates for eradiation of esophageal intestinal metaplasia (BE) are about 53–84%. These results are comparable to radiofrequency ablation, which is the reference standard for BE ablation. These provide a distinct advantage for Cryo over superficial forms of endoscopic ablation such as radiofrequency ablation or argon plasma coagulation. Adverse events have also been uncommon, mainly due to strictures (9%, all easily dilated), and very rare perforations during early studies. Cryo may also be a viable outpatient endoscopic treatment option for patients with obstructing tumors and cancers that recur after chemotherapy and/or radiation therapy. Compared to alternative endoscopic cancer palliative therapies for EAC such as photodynamic therapy (that results in extreme photosensitivity, greater pain and more frequent esophageal strictures) and esophageal stenting (which causes chest pain and does not treat the primary tumor), Cryo is an attractive viable palliative treatment option. One retrospective multicenter study of liquid nitrogen Cryo reported complete regression of BE HGD of 100%, luminal cancer in 75% with no serious adverse events and 2 year follow-up (Gossain et al., Gastrointest Endosc 2013). Finally, Cryo may also be considered for local treatment of high risk inoperable patients with BE adenocarcinomas in non-lifting nodular lesions, depressed and ulcerated lesions (Paris IIc and III class), or deep margin positive invasive EAC following endoscopic mucosal resection. Device development is ongoing, including improvements of existing devices and clinical trials on new devices such as a focal and circumferential cryotherapy balloon. Clinical trials are ongoing. Endoscopic cryotherapy has a great potential for mainstream clinical therapeutic use in early studies but more data are needed, particularly on optimal dosimetry, safety and cost-effectiveness compared with other existing therapies, long term outcomes, and quality of life.