With the advent of molecularly targeted drugs, the treatment of metastatic renal cell carcinoma (mRCC) has advanced considerably, and sequential treatment with different molecularly targeted drugs has become a common treatment modality. However, it is still a challenge to optimize the sequence of targeted drugs to benefit patients more. Recently, Christian et al. from the University of Regensburg, Germany, prospectively evaluated the efficacy and safety of different sequences of the multikinase inhibitors sorafenib (So) and sunitinib (Su) (So-Su vs. Su-So) in the treatment of mRCC. Both regimens were found to be similarly effective in the treatment of mRCC, with no significant differences. The article was published in a recent issue of European Urology. A total of 365 patients with mRCC were randomized to the So-Su (182) and Su-So (183) regimens, with sorafenib at 400 mg bid and sunitinib at 50 mg qd in a 4/2 regimen (i.e., 1 week of treatment with 2 weeks off for 4 weeks). Second-line therapy was initiated when patients experienced disease progression or intolerable drug toxicity during first-line therapy. The primary metric for the study was progression-free survival (PFS) after treatment with different regimens, which is the time between the start of treatment and the observation of disease progression or the occurrence of death from any cause. Other indicators included overall survival and the safety of the drug. The results showed no significant difference in overall PFS between the So-Su and Su-So groups, with a mean PFS of 12.5 months and 14.9 months, respectively (HR = 1.01). Overall survival was also similar between the two treatment groups, at 31.5 months and 30.2 months, respectively (HR = 1.00). However, more patients in the So-Su group underwent second-line treatment (57% vs. 42%). Overall there was little difference in the incidence of adverse events between the two groups, with diarrhea (54%) and hand-foot syndrome (39%) being the most common adverse events with sorafenib as first-line treatment, and diarrhea (40%) and malaise (40%) being the most common with sunitinib. Overall, this study is the first to prospectively evaluate the efficacy and safety of So-Su versus Su-So treatment regimens. There were no significant differences between the two groups in terms of overall PFS, overall survival or safety. These results suggest that both regimens are similarly effective and that sequential treatment with molecularly targeted agents can significantly improve patient outcomes (mean overall survival of approximately 30 months). In addition, the optimal sequence of molecularly targeted drugs needs to be further investigated.