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To provide an overview of the recent advances in the understanding of the molecular mechanisms governing the tumour suppressor functions of the von Hippel-Lindau protein.von Hippel-Lindau is a vital component of an E3 ubiquitin ligase complex involved in the oxygen-dependent targeting of hypoxia-inducible factor for ubiquitin-mediated destruction. Recent reports have linked von Hippel-Lindau to the regulation of diverse biological processes including cell adhesion, extracellular matrix assembly and ciliogenesis in a manner dependent and/or independent of hypoxia-inducible factor.The tumour suppressor function of von Hippel-Lindau has remained hypoxia-inducible factor-centric since the discovery of von Hippel-Lindau as a bona fide negative regulator of the ubiquitous oxygen-sensing pathway. Emerging evidence supports this hypothesis with the elucidation of fundamental cellular processes deregulated upon the inactivation of the von Hippel-Lindau–hypoxia-inducible factor pathway, but has also proved compelling on the hypoxia-inducible factor-independent tumour suppressor role of von Hippel-Lindau. These and continuing studies into the molecular pathways and mechanisms governing the tumour suppressor functions of von Hippel-Lindau will ultimately afford new avenues for anticancer strategies for the improved treatment of a diverse array of cancers.