Although over 70% of patients with metastatic renal cell carcinoma (RCC) respond to initial therapy with tyrosine kinase inhibitors (disease control rate 70-80%), approximately 20-30% of patients do not respond to first-line therapy and progress within ≤3 months. Understanding the mechanisms of resistance to targeted therapies is vital in the development of prospectively defined sequences and because the choice of first-line therapy determines that of second and subsequent line therapy, identification of the optimal first-line therapy is a priority for clinicians treating patients with metastatic RCC. By preselecting those patients most likely to respond to antivascular endothelial growth factor therapy, clinicians can begin to optimize therapeutic strategies. This review focuses on primary antivascular endothelial growth factor-refractory patients and the move towards individualizing treatment for RCC. The authors include a review of the growing number of studies, as yet retrospective, which provide important information on the group of primary refractory patients with advanced RCC for whom the prognosis is not good. First, the percentage of primary refractory patients (26%) is in agreement with disease control rate - the sum of objective responses and disease stabilization, observed in registration studies for a range of tyrosine kinase inhibitors. Second, the prognosis for these patients is poor as they do not respond to first-line nor to second-line therapy, and changing the mechanism of action (with inhibition of mTOR pathway) does not appear to produce additional benefits. Third and most importantly, the results of these studies demonstrate the need to better characterize the mechanism of primary resistance to current therapeutic agents with the ultimate aim of developing a therapeutic strategy for this important subgroup of patients.