Prior to 2005, many patients with advanced renal cell carcinoma (RCC) were diagnosed, observed and eventually palliated, without ever receiving systemic therapy to slow the tempo of their disease. Renal cancers were both radio- and chemo-resistant, leaving few treatment options. Study of the rare hereditary condition, Von Hippel Lindau disease, led to the discovery of the key role of angiogenesis-related factors in sporadic clear cell carcinomas and resulted in the development of inhibitors targeting key steps in this pathway. Small molecule multi-targeting tyrosine kinase inhibitors such as sunitinib, sorafenib and pazopanib, improved progression-free survival and provided durable disease stability, despite lacking curative potential. These agents, along with targeting of alternative growth pathways with everolimus, now form the backbone of treatment for Australian patients with advanced RCC. While newer immunotherapy approaches hold significant promise and may one day supersede all other therapies for some patients, it is likely that targeted therapies will continue to hold an important role. Clinicians therefore need to remain familiar with the use of these agents and with the significant class-effect and drug-specific toxicities that can occur.