Clear cell renal cell carcinoma (ccRCC), the most common subtype of kidney cancer, is characterised by biallelic inactivation of the von Hippel-Lindau (VHL) tumour suppressor gene, and inherited loss-of-heterozygosity of VHL underlies the eponymous hereditary cancer syndrome. The VHL protein product, pVHL, is the substrate recognition component of an E3 ubiquitin ligase complex responsible for targeting Hypoxia Inducible Factors (HIFs) for proteasomal degradation. Accumulation of the HIF-2α isoform, in particular, drives renal tumourigenesis. VHL loss occurs at an early stage of ccRCC development, often several years before the clinical manifestation of disease, and so is observed throughout the entire mass of both primary and metastatic tumours. Therapeutic approaches which specifically target cells harbouring VHL mutations could therefore provide effective anti-tumour responses with minimal off-target effects. In this thesis, I undertake CRISPR/Cas9 screens in ccRCC cell lines deficient in VHL, and in paired VHL-reconstituted cells, aiming to identify genetic vulnerabilities of cells lacking functional pVHL. These reveal a synthetic lethal relationship between Core Binding Factor β (CBF-β) and pVHL. While CBF-β is critical for normal osteogenesis and haematopoiesis, little is known about its role in renal tissue. CBF-β classically stabilises the Runt related transcription factors (RUNX1-3) to improve their transcriptional efficiency. However, using a variety of cell biology techniques, I demonstrate that knockout of CBFB is lethal in cells lacking VHL through a mechanism which is independent of both direct CBF-β-RUNX binding and the high HIF activity of VHL-null cells. In addition, RNA sequencing and mass spectrometry reveal that CBF-β depletion causes a widespread upregulation of interferon (IFN)-stimulated genes (ISGs), although this does not contribute to the cell death phenotype. Rather than occurring through a canonical IFN response, CBF-β loss-induced ISG expression relies on the direct transcriptional activity of IFN Regulatory Factor 3 (IRF3) and its stimulation via STING. Together, these results reveal a novel requirement of VHL-mutant ccRCC cells for CBF-β, loss of which provokes cell death and increases ISG expression. Besides triggering direct tumour cell killing, depletion of CBF-β may present a strategy to reactivate anti-tumour immune surveillance in renal cancer.