Clear-cell renal cell carcinoma (RCC) is characterized by the loss of von Hippel-Lindau disease protein and the resultant dysregulation of the vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR), platelet-derived growth factor-beta (PDGF-beta)/PDGF receptor-beta (PDGFR-beta), and transforming growth factor-alpha (TGF-alpha)/epidermal growth factor receptor (EGFR)/Raf pathways, which contribute to angiogenesis, lymphangiogenesis, and tumor cell growth and survival. Significant advances in the treatment of clear-cell RCC have been derived from agents that target these pathways, including the multiple-kinase inhibitors (MKIs) sorafenib, sunitinib, and AG013736, which target multiple VEGFRs as well as PDGFR-beta. Sorafenib has the added advantage of inhibiting multiple different Raf isoforms, which enables it to target TGF-alpha/EGFR signaling and may also enhance its inhibition of VEGFR and PDGFR-beta. This review will examine the recent advances in our understanding of the biology of clear-cell RCC and show how those advances have helped delineate new targets of opportunity for treatment. It will also present the early clinical results of agents that target the pathways dysregulated in clear-cell RCC, with special emphasis on sorafenib and the other active MKIs, and will describe the scientific rationales for ongoing and future sorafenib-based combination therapy trials in RCC.