VHL (Von Hippel–Lindau) forms a complex along with elongin B and elongin C (protein homologous to Skp1), cullin 294 and the small RING finger protein Rbx1. VHL binds to elongin C through a special motif, the BC box, which is necessary and sufficient for this interaction. VHL is substrate recognition subunit of the CRL2 or cullin 2-elongin B-elongin C (CBC) family of RING finger E3 ubiquitin ligases, that targets the alpha subunits of the heterodimeric transcription factor hypoxia inducible factor (HIF) for ubiquitylation and proteasomal degradation in an oxygen-dependent manner. Besides HIFα, the growing list of VHL targets include activated epidermal growth factor receptor, RNA polymerase II subunits RPB1 and hsRPB7, atypical protein kinase C, Sprouty2, β-adrenergic receptor II and Myb-binding protein p160. These substrates might also be important for tumor growth and can provide a new direction for next generation therapeutic approaches.[1]