Outcomes for oesophageal cancer are poor, currently 60% die within a year of diagnosis. The early dissemination of the disease means that systemic treatments are critically important for successful management. However progress has been slow and the development of targeted agents and predictive biomarkers together with a molecular pathological classification of the disease to underpin precision medicine approaches has lagged behind other tumour types. In this talk I will discuss the factors limiting progress including the difficulties encountered with current approaches to clinical research, the need for improved models, and some of the key unresolved mechanistic questions that are relevant to the clinical biology of the disease and that offer potential for therapeutic translation. I will discuss and illustrate how we are addressing these issues in my group and the strong opportunities for physician and scientist collaborations this presents.