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The review will examine the recent advances in our understanding of the genetic and molecular events that shape this cancer, and overview the emerging targeted therapies that have altered the landscape for renal cell carcinoma (RCC) patients.The incidence of RCC continues to rise, making it the 7th and 8th most common cancer among men and women in the US, respectively. Von Hippel-Lindau (VHL) gene loss is an important factor in the development of clear cell RCC, however: loss of VHL can result in tumors which express both HIF1 and HIF2, or HIF2 alone, correlating with distinct pathway activities. Invasive tumors demonstrating loss of VHL consistently demonstrate additional genetic changes, which appear to be essential for tumor progression. Targeted therapies have demonstrated improvements in overall survival. New ways to radiographically measure the tumor response to these treatments may provide additional information about a drug's activity in an individual patient. Vascular endothelial growth factor receptor tyrosine kinase inhibitors are still being investigated in the adjuvant setting.The field of RCC biology continues to rapidly change. As new targeted strategies to control this cancer evolve, so do both the clinical strategies, and the strategies to measure response and predict outcome.