Sequencing decisions in advanced renal cell carcinoma are likely to become more difficult when new targeted agents are approved for first and subsequent lines of therapy. Approximately 70% of patients benefit from targeted therapy before progression, of which 20% can be described as short-term responders (progression-free survival: <6 months) and 50% as long-term responders (progression-free survival: >6 months). The remaining 30% show either no response (20%) or are intolerant to treatment (10%). The challenge is to establish the optimal second-line agent for over 70% of patients who progress following initial response to a first-line tyrosine kinase inhibitor. As it is impossible to define the optimal second-line therapy for every patient, it is suggested that age and comorbidities of the patient, the sites of disease and the side effects of previous therapies be taken into account in order to optimize the use of different agents sequentially.