Abstract Renal cell carcinoma (RCC) is a heterogeneous malignancy whose incidence rate has notably increased in recent years without any evident reason. Traditionally, RCC has been resistant to classic treatments (chemothera- py, radiotherapy and hormonal therapy), with only a small percentage of patients benefiting from cytokine therapy. Different hereditary syndromes have been associated with RCC, Von Hippel Lindau (VHL) being the most impor- tant syndrome. Understanding key molecular pathways implicated in the tumorigenesis of RCC has crystallised in the development of more effective therapies. Specifically, drugs targeting VEGF (bevacizumab, sunitinib, sorafenib, axitinib, pazopanib) and PI3K-mTOR (temsirolimus and everolimus) have become the cornerstone of renal cancer treatment. Keywords Renal cell carcinoma · Molecular basis · Targeted therapies · Key pathways Introduction Renal cell carcinoma (RCC) incidence has increased over recent years, especially in industrialised areas, without any clear reason. Increasing use of computed tomography and other imaging techniques allows diagnosis at earlier stages, often as incidentalomas, however increased RCC incidence cannot be explained by this reason alone. Kidney cancer is a heterogeneous malignancy; it in- cludes different tumours, with different gene alteration profile, histology, clinical evolution and treatment re- sponse. Metastatic RCC is highly resistant to conventional on- cologic treatments including chemotherapy, radiotherapy and hormonal therapies. Classically, cytokine-based im- munotherapy has been the only effective treatment for RCC. Recent advances towards the understanding of the molecular basis of kidney cancer have crystallised in effective therapies, based on specific molecular tar- gets. As a result, kidney cancer has become a model for translational research. In this review we will focus on how a better understanding of hereditary syndromes and tumour biology has fuelled the development of new treat- ments (Fig. 1). Hereditary syndromes Von Hippel Lindau (VHL) The most important molecular disorder in clear-cell renal carcinoma involves the VHL tumour suppressor gene. Von Hippel Lindau syndrome is an autosomal dominant disease with high penetrance (over 90%), which is characterised by the inactivation of the VHL tumour suppressor gene locat- ed on chromosome 3p25 [1, 2]. Its incidence has been es- timated to occur in 1 out of 36,000 live births [3]. Clinical manifestations of this syndrome consist of haemangioblas- tomas of the central nervous system, especially cerebellum or spinal cord, retinal angiomas, visceral cysts and solid tumours. Solid tumours include pheochromocytomas, pan- C. Suárez · R. Morales · E. Muñoz · J. Rodón · C.M. Valverde · J. Carles () Department of Medical Oncology Vall d’Hebrón University Hospital Passeig de la Vall d’Hebrón, 119-129 ES-08035 Barcelona, Spain e-mail: jocarles@vhebron.net Clin Transl Oncol (2010) 12:15-21 DOI 10.1007/s12094-010-0461-4 EDUCATIONAL SERIES Green Series Molecular basis for the treatment of renal cell carcinoma Cristina Suárez · Rafael Morales · Eva Muñoz · Jordi Rodón · Claudia M. Valverde · Joan Carles Received: 2 October 2009 / Accepted: 3 November 2009 MOLECULAR TARGETS IN ONCOLOGY