<p><b>Background:</b> The worldwide incidence of esophageal cancer has greatly increased over the past few decades making it the sixth deadliest cancer. The disease is often detected in advanced stages when surgery is no longer an option. The standard treatment in these situations is combined chemoradiotherapy, by employing drug cocktails that lead to optimal treatment outcomes both from the perspective of tumor control and normal tissue toxicity.</p> <p><b>Methods:</b> The aim of this work was to collate the existing trials and clinical studies reported on non-operable esophageal cancer and to analyze the results based on treatment outcomes after various drug combinations.</p> <p><b>Results:</b> Of all drug combinations, cisplatin/5-FU is the most well established chemotherapy regimen for esophageal cancer as both neoadjuvant therapy, an alternative option to surgery, and for palliative purposes. Although this regimen is associated with the most toxicity, it also appears to have the best survival benefit and relief of symptoms.</p> <p><b>Conclusions:</b> More research is warranted to further increase the therapeutic ratio in non-operable esophageal cancers.</p