Many improvements have been made in the treatment of oesophageal cancer. Surgical techniques have been refined, multimodality treatment has become the standard of care and nationwide quality audits have been introduced. Nevertheless, there are some persevering challenges in the treatment of oesophageal cancer and its complications: 1. with current staging modalities, even after radical surgery, many patients suffer from early recurrence (“challenge to stage”) ; 2. more than half of the patients who undergo surgery will still die from oesophageal cancer (“challenge to cure”) ; 3. complications after surgery cannot always be treated early and appropriately (“challenge to rescue”) ; 4. surgery alone, without preceding neoadjuvant therapy, too often has the disadvantage of involved surgical resection margins (“challenge to resect”); 5. there is a striking rise in the incidence of oesophageal adenocarcinoma, especially in the Western hemisphere, which is only partly understood (“challenge to prevent”). This thesis includes clinical studies that address these issues which are still present in treating this devastating disease.