The life expectancy in metastatic renal cell carcinoma patients treated with targeted therapies can be influenced by the time spent on treatment, and the current focus of clinical research in this field appears to be on extending the time on treatment while limiting toxicities. It has been proposed that a strategy based on the sequential administration of two tyrosine kinase inhibitors could result in unacceptable cumulative toxicity for many metastatic renal cell carcinoma patients, while switching to a mTOR inhibitor does not. However, a definite consensus on this issue has not been reached. As very little information from head-to-head studies is available, clinicians have to base their treatment decisions on existing evidence, with an obvious preference for high-quality studies. Some recent studies have provided new insights into the issue of cumulative toxicity of second-line targeted therapies in metastatic renal cell carcinoma patients. In this article, we discuss the evidence emerging from the randomized AXIS and RECORD-3 trials.