Simple SummaryOver the last decade there has been a significant increase in the number of therapies that activate the host’s immune system to target and eliminate renal cell carcinoma (RCC) tumors. The superior efficacy of these agents demonstrates that host control of RCC requires a robust and effective immune response. Given the increasing incorporation of immune activating agents into routine clinical practice for the management of RCC, it is important for researchers and clinicians to understand the characteristics of the immune microenvironment in RCC tumors. The purpose of this review is to describe the concepts of the anti-tumor immune response to RCC and to provide a detailed summary of the current understanding of the immune response to RCC tumor development and progression. Additionally, this article explores how components of the immune microenvironment are being used to predict response to therapy and patient survival.AbstractScientific understanding of how the immune microenvironment interacts with renal cell carcinoma (RCC) has substantially increased over the last decade as a result of research investigations and applying immunotherapies, which modulate how the immune system targets and eliminates RCC tumor cells. Clinically, immune checkpoint inhibitor therapy (ICI) has revolutionized the treatment of advanced clear cell RCC because of improved outcomes compared to targeted molecular therapies. From an immunologic perspective, RCC is particularly interesting because tumors are known to be highly inflamed, but the mechanisms underlying the inflammation of the tumor immune microenvironment are atypical and not well described. While technological advances in gene sequencing and cellular imaging have enabled precise characterization of RCC immune cell phenotypes, multiple theories have been suggested regarding the functional significance of immune infiltration in RCC progression. The purpose of this review is to describe the general concepts of the anti-tumor immune response and to provide a detailed summary of the current understanding of the immune response to RCC tumor development and progression. This article describes immune cell phenotypes that have been reported in the RCC microenvironment and discusses the application of RCC immunophenotyping to predict response to ICI therapy and patient survival.