jats:titleAbstract</jats:title>jats:pInactivation of the jats:italicVHL</jats:italic> (Von Hippel Lindau) tumour suppressor has long been recognised as necessary for the pathogenesis of clear cell renal cancer (ccRCC); however, the molecular mechanisms underlying transformation and the requirement for additional genetic hits remain unclear. Here, we show that loss of VHL alone results in DNA replication stress and damage accumulation, effects that constrain cellular growth and transformation. By contrast, concomitant loss of the chromatin remodelling factor PBRM1 (mutated in 40% of ccRCC) rescues VHL-induced replication stress, maintaining cellular fitness and allowing proliferation. In line with these data we demonstrate that combined deletion of jats:italicVhl</jats:italic> and jats:italicPbrm1</jats:italic> in the mouse kidney is sufficient for the development of fully-penetrant, multifocal carcinomas, closely mimicking human ccRCC. Our results illustrate how jats:italicVHL</jats:italic> and jats:italicPBRM1</jats:italic> co-operate to drive renal transformation and uncover replication stress as an underlying vulnerability of all jats:italicVHL</jats:italic> mutated renal cancers that could be therapeutically exploited.</jats:p>