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| The incidence of renal cell carcinoma (RCC) is increasing and outcomes remain poor. One-third of patients with localized disease will relapse, and 5-year survival for patients with metastatic disease is less than 10%. No molecular test is currently available to identify which patients who have undergone ‘curative’ surgery will relapse, and which patients will respond to targeted therapy. Some well characterized biochemical pathways, such as those associated with von Hippel-Lindau disease, are aberrantly regulated in RCC and are associated with histological subtype, but the understanding of these pathways contributes little to the clinical management of patients with RCC. Gene expression and sequencing studies have increased our understanding of the genetic basis of the disease but have failed to establish any unified classification to improve molecular stratification or to predict which patients are likely to relapse or respond to targeted therapy. Instead, they have served to highlight that RCC is heterogeneous at histological, morphological, and molecular levels, and that novel approaches are required to resolve the complexity of RCC prognostication and prediction of treatment response.