Renal cell carcinoma (RCC) is the most common type of kidney cancer, accounting for over 90% of kidney cancers. It encompasses more than 10 histological and molecular subtypes, with clear cell RCC (ccRCC) being the most common and responsible for most cancer-related deaths. While somatic VHL mutations have been known for some time, recent genomic studies have identified mutations in epigenetic regulatory genes and shown marked intratumour heterogeneity, which may have prognostic, predictive, and therapeutic relevance. Localized RCC can be treated with surgery, while metastatic RCC is resistant to conventional chemotherapy. However, over the past decade, significant advances in treatment of metastatic RCC have been made, with targeted agents such as sorafenib, sunitinib, bevacizumab, pazopanib, and axitinib, which inhibit vascular endothelial growth factor (VEGF) and its receptor (VEGFR), and everolimus and temsirolimus, which inhibit mTOR complex 1, being approved. Since 2015, agents with additional targets aside from VEGFR have been approved, such as cabozantinib and lenvatinib; immunotherapies such as nivolumab have also been added to the armamentarium for metastatic RCC. This review provides an overview of the molecular biology of RCC, with a focus on ccRCC, as well as updates to complement current clinical guidelines and an outline of potential future directions for RCC research and therapy. RCC is a heterogeneous group of cancers derived from renal tubular epithelial cells, and key advances in histopathological and molecular characterization have led to major revisions in its classification. Major subtypes with ≥5% incidence are clear cell RCC (ccRCC), papillary RCC (pRCC), and chromophobe RCC (chRCC). The remaining subtypes are very rare. ccRCC is the most common subtype and accounts for the majority of kidney cancer deaths and is the focus of this Primer. ccRCC is the most common subtype and accounts for the majority of kidney cancer deaths and is the focus of this Primer. The incidence of RCC is highest in the Czech Republic, with age-standardized annual rates of 22.1 and 9.9 new cases per 100,000 men and women, respectively, over the period 2003–2007. The incidence is also very high in the Baltic and Eastern European countries, although the reasons for this excess are not known. Overall, incidence rates have been increasing over time in most populations, but mortality rates have levelled off or are decreasing since the 1990s. This divergent pattern of increasing incidence and decreasing mortality is particularly evident in developed countries. For example, analyses within the SEER database indicate that the increase in RCC incidence is confined toRenal cell carcinoma (RCC) is the most common type of kidney cancer, accounting for over 90% of kidney cancers. It encompasses more than 10 histological and molecular subtypes, with clear cell RCC (ccRCC) being the most common and responsible for most cancer-related deaths. While somatic VHL mutations have been known for some time, recent genomic studies have identified mutations in epigenetic regulatory genes and shown marked intratumour heterogeneity, which may have prognostic, predictive, and therapeutic relevance. Localized RCC can be treated with surgery, while metastatic RCC is resistant to conventional chemotherapy. However, over the past decade, significant advances in treatment of metastatic RCC have been made, with targeted agents such as sorafenib, sunitinib, bevacizumab, pazopanib, and axitinib, which inhibit vascular endothelial growth factor (VEGF) and its receptor (VEGFR), and everolimus and temsirolimus, which inhibit mTOR complex 1, being approved. Since 2015, agents with additional targets aside from VEGFR have been approved, such as cabozantinib and lenvatinib; immunotherapies such as nivolumab have also been added to the armamentarium for metastatic RCC. This review provides an overview of the molecular biology of RCC, with a focus on ccRCC, as well as updates to complement current clinical guidelines and an outline of potential future directions for RCC research and therapy. RCC is a heterogeneous group of cancers derived from renal tubular epithelial cells, and key advances in histopathological and molecular characterization have led to major revisions in its classification. Major subtypes with ≥5% incidence are clear cell RCC (ccRCC), papillary RCC (pRCC), and chromophobe RCC (chRCC). The remaining subtypes are very rare. ccRCC is the most common subtype and accounts for the majority of kidney cancer deaths and is the focus of this Primer. ccRCC is the most common subtype and accounts for the majority of kidney cancer deaths and is the focus of this Primer. The incidence of RCC is highest in the Czech Republic, with age-standardized annual rates of 22.1 and 9.9 new cases per 100,000 men and women, respectively, over the period 2003–2007. The incidence is also very high in the Baltic and Eastern European countries, although the reasons for this excess are not known. Overall, incidence rates have been increasing over time in most populations, but mortality rates have levelled off or are decreasing since the 1990s. This divergent pattern of increasing incidence and decreasing mortality is particularly evident in developed countries. For example, analyses within the SEER database indicate that the increase in RCC incidence is confined to