Von Hippel–Lindau (VHL) disease is caused by germline mutation of the VHL tumour suppressor gene. Patients frequently develop multiple nervous system tumours, denominated haemangioblastomas. Analysis of affected autopsy tissues suggests that tumourigenesis propagates from developmentally arrested, embryonic cells and progresses with consistent architectural, cytological, and molecular sequences similar to haemangioblastic formation and differentiation in the embryo. In this study, we analysed 156 nervous system tumours, 139 of which had been surgically resected from 83 VHL patients. We demonstrate that large tumours consistently contain epithelioid components characteristic of haemangioblastic differentiation in comparison to small tumours that solely display a poorly differentiated, mesenchymal structure. We further show exclusive activation of HIF2α in both small mesenchymal tumours and the mesenchymal component of large tumours, whereas activation of HIF1α is associated with epithelioid structure. We also show that the MIB1 proliferative index is variably increased in the epithelioid component of large tumours, with extramedullary haematopoiesis foci within the epithelioid component at 100%. These data provide compelling evidence that nervous system tumourigenesis in VHL disease represents a protracted process of haemangioblastic proliferation and differentiation that parallels haemangioblastic formation and differentiation in the embryo. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.