The outcome in metastatic renal cancer remains poor with an overall survival at 5 years of less than 10%. However, molecular pathology in kidney cancer has developed extensively in the few last years, providing a basis for new systemic therapies including antiangiogenic drugs and mTOR inhibitors. Use of these targeted therapies in metastatic disease has improved the prognosis but still in a too-limited range, with a lack of consistent predictive biomarkers. The multiple entities of renal tumors add complexity to the research of biomarkers and the design of clinical trials. This review aims to focus on pathways in renal cancer (VHL/HIF, mTOR, c-MYC, c-MET, and immune response) in the respective tumor subtypes, accounting for the effects of targeted therapies and providing the framework to search for relevant predictive biomarkers and propose new trials. This overview underscores that the pathways are often intermingled and common (at least partially) to the different tumor subtypes.