Attempts to predict outcome in patients with metastatic clear-cell renal cell carcinoma (RCC) have conventionally been based on pretherapy clinical factors such as performance status, disease-free interval, number of metastatic sites and several laboratory variables. These factors were developed before the era of VEGF-targeted therapy. Recent analysis from trials with anti-VEGF agents indicate that these factors continue to be of major importance in patient prognostication. Additionally, several serum and molecular markers, many of which relate to certain alterations of the von Hippel-Lindau pathway, are currently being investigated. Responses to VEGF-targeted agents appear to be related to a greater modulation of serum VEGF and soluble VEGF receptor levels. The impact of von Hippel-Lindau gene status on response to VEGF-targeted therapy was tested in a large study and was not found to predict a higher response rate to these agents. However, a subset of von Hippel-Lindau mutations that predict a 'loss of function' of the von Hippel-Lindau gene seem to have the best response to these agents. Future prognostic models will incorporate molecular markers with clinical variables to refine prognosis and prediction in metastatic clear-cell RCC patients treated with novel VEGF-targeted agents. These models, if externally and prospectively validated, will culminate in the rational selection of patients for specific VEGF-directed therapeutics.