For the past decade, advanced renal cell carcinoma (RCC) has been at the forefront of oncologic innovation. Our rapidly evolving understanding of the molecular and genetic basis of RCC has revolutionized the management of advanced RCC; 10 novel molecular targeted agents and immune checkpoint inhibitor have received U.S. Food and Drug Administration approval for treatment of advanced RCC in a little over a decade. Amid this progress, imaging has assumed a central role in metastatic surveillance and follow-up of advanced RCC. State-of-the-art knowledge of the molecular basis of RCC and its treatment and imaging will help ensure that the radiology community remains relevant and central in the care of patients with advanced RCC. This article will review developments in management of advanced RCC from a radiologist's perspective to highlight our clinical role. It will describe how the underlying molecular mechanisms of RCC provide specific targets for novel anticancer agents. The relationship between the mechanisms of action of these novel anticancer agents and the imaging appearance of tumor response will be discussed, along with the available tumor response criteria and their strengths and weaknesses, thus assisting radiologists in response assessment in the setting of clinical trials or routine practice. The class- and drug-specific toxicities and complications associated with the novel anticancer agents will be summarized, since these are frequently missed or misinterpreted and require the radiologist's input in prompt detection and management. The potential role of radiogenomics and texture analysis in the management of advanced RCC will also be discussed. © RSNA, 2017.