Pancreatic ductal carcinoma still is an aggressive disease with a fatal prognosis due to late diagnosis and resistance to pharmacological and surgical treatments. Molecular investigations of pancreatic cancer are complicated by the restricted accessibility of the organ for biopsies. However, recent studies have indicated that pancreatic cancer is a multi-stage process resulting from the accumulation of genetic changes in the somatic DNA of normal cells. These molecular alterations, including overexpression of receptor-ligand systems, oncogene activation and loss of tumour suppressor genes, leads to a profound disturbance in cell cycle regulation and continuous growth. The molecular findings are now integrated in a pancreatic tumour progression model, with genetically and morphological defined precursor lesions. However, it remains unclear whether the initial target cells of this cancer develop from ductal or acinar cells. This review will present recent emerging questions on the biology of pancreatic cancer with particular emphasis on the cell origin and tumour microenvironment.