Pre-surgical systemic therapy with targeted molecular agents is an attractive option as an approach to the treatment of patients with renal cell carcinoma. This treatment strategy offers a rational approach for selecting patients with metastatic disease who are most likely to benefit from cytoreductive nephrectomy, but also allows access to treated tumour tissue to study the molecular mechanisms of response and resistance. In patients with locally advanced disease, this strategy offers the potential for improved resectability and timely delivery of systemic therapy to treat subclinical metastatic disease. Preliminary evidence indicates that the use of targeted therapies before nephrectomy is safe. Reliable therapy-specific prognostic biomarkers are needed for the optimal integration of aggressive surgical intervention and systemic therapy to maximize the oncological benefits for the patient.