Oesophageal cancer remains one of the least explored malignancies. However, in recent years its increasing incidence and poor prognosis have stimulated interest from the cancer community to understand the pathways to the initiation and progression of the disease. Critical understanding of the molecular processes controlling changes in stem cell fate and the cross-talk with their adjacent stromal neighbours will provide essential knowledge on the mechanisms that go awry in oesophageal carcinogenesis. Advances in linage tracing techniques have represented a powerful technique to start understanding changes in oesophageal cell behaviour in response to mutations and mutagens that favour tumour development. Environmental cues also constitute an important factor in the aetiology of oesophageal cancer. The oesophageal epithelium is a tissue exposed to harsh environmental conditions that not only damage the DNA of epithelial cells but also result in an active stromal reaction, promoting tumour progression. Ultimately, cancer represents a complex interplay between malignant cells and their microenvironment. Indeed, increasing evidence suggests that the accumulation of somatic mutations is not the sole cause of cancer. Instead, non-cell autonomous components, such as the stroma, can significantly contribute from the earliest stages of tumour formation. The realisation that stromal cells play an important role in cancer has transformed this cellular compartment into an attractive and emerging research field. It is becoming increasingly apparent that the tumour microenvironment provides unique opportunities to identify early diagnostic and prognostic markers, as well as potential therapeutic strategies that may synergise with those targeting tumour cells. This chapter compiles recent observations on oesophageal epithelial stem cell biology, and how environmental and micro-environmental changes may lead to oesophageal disease and cancer.