The vascular endothelial growth factor (VEGF) pathway blockers and mammalian target of rapamycin (mTOR) inhibitors have dramatically improved the treatment options and outcome for patients with advanced renal cell carcinoma (RCC). However, because the vast majority of patients will still succumb to their disease, novel treatment approaches are still necessary. Efforts to identify novel therapeutic target treatments are focused on better understanding unique aspects of tumor cell biology guided the Cancer Genome Atlas analyses and the interaction of the tumor with its microenvironment. Areas of promising investigation include a) the identification of mechanisms of acquired resistance to VEGF pathway inhibition and developing agents targeting these in combination with VEGF receptor (VEGFR) pathway blockade; b) the identification of novel therapeutic targets, particularly for patients with VEGF pathway blocker refractory disease; and c) the development of novel immunotherapies, particularly those involving checkpoint inhibitors used alone or in combination with other immunotherapies of VEGF pathway blockers. Specific targets or agents of interest include angiopoietins (trebaninib), c-Met (cabozantinib), activin receptor-like kinase-1 (ALK-1; dalantercept), interleukin (IL)-8, and HDM2 for acquired resistance to VEGF pathway inhibition; hypoxia inducible factor-2 alpha (HIF-2 alpha), TORC1/2, and the Hippo pathway for novel targets, and PD1 and PDL1 antibodies given either alone or in combination with other checkpoint inhibitors, other immunotherapies, or VEGF pathway blockers for novel immunotherapies. In addition, the application of genetic, immunologic, or other biomarkers developed in the context of this research has the potential to select patients with specific tumor types for therapy targeted to specific vulnerabilities within the tumor or tumor microenvironment. Together, these developments should enable the transition to a new era of rational and more effective therapy for patients with advanced RCC.