The introduction of targeted agents over last decade has represented an important turning point in the treatment of several tumor types, allowing oncologists to achieve novel therapeutic goals. This particularly applies to metastatic renal-cell carcinoma (mRCC), an orphan disease accounting for 3% of malignancies in adults that is largely unresponsive to any former therapeutic option[1]. The use of tyrosine kinase inhibitors (TKIs) targeting both angiogenesis and tumor cell proliferation pathways proved to be extremely useful in terms of prolongation of both progression-free survival (PFS) and overall survival (OS) [1-2]. As a result several TKIs have been developed and are now available for mRCC patients. All of them proved to be effective individually as compared to placebo or interferon, primarily as front-line treatments. However, none of these agents may be considered superior to the others and, accordingly, the treatment choice is driven by prognostic factors, patients comorbidity and drug safety profiles [3]. Unlike the experience for many other tumors’ treatments with TKIs, in mRCC clinical results showed that no cross-resistance among different drugs seems to exist since. That is, at disease recurrence, patients are able to benefit from treatment with an additional TKI from the same class of agents [4]. This evidence led many investigators to turn routinely to this practice which resulted in further prolongations of PFS. In this regard, most information comes from the sequential use of sorafenib (SO) followed by sunitinib (SU), or vice versa, because they were the two TKIs that were first approved. Retrospective, series, though methodologically limited by the presence of different patient population sample sizes, have been carried out [4]. However, the results were inconclusive. Despite the lack of any reliable predictive biomarker and clinical evidence, it has been hypothesized that the sequence SO followed by SU may be a better approach. The rationale was based on the theory that it is preferable to start with an agent with a higher antiangiogenic profile (SO) and then use the one with a more striking anti-proliferation property (SU) at disease progression [4]. To put an end to this uncertainty, a prospective randomized openlabel study evaluating efficacy and safety of the sequence SO/SU versus SU/SO was carried out by a German Cooperative Study Group (SWITCH study ClinicalTrials.gov identifier: NCT00732914). Results have been recently presented at the 2014 ASCO GU Symposium. The trial, which enrolled 365 patients, was powered to detect a 47% increase in PFS with the sequence SO/SU compared to SU/SO. The study failed to fulfill the primary objective since no statistically significant difference in PFS was observed across the arms (HR 1.01; p=0.54). Likewise, there was no statistically significant difference in OS (HR 0.997, p=0.49) and in overall disease control rate (DCR) (72 and 67% respectively). The authors concluded that both drugs provide overall benefit regardless of the sequence of administration [5]. Can we consider this outcome as the Gospel truth and, consequently, state that the order of administration does not matter? Some concerns regarding the study design in this report are worth considering. First of all, the 47% increase in PFS of the sequence SO/SU over SU/SO appears as an extremely ambitious target, and we wonder if this choice was due to i) the negative influence of the retrospective data which misguided the investigators, ii) the need to limit as much as possible the sample size for reasons of accrual, or iii) the reliance on the less favorable toxicity profile of sunitinib. Perhaps a noninferiority design of SO/SU as compared to SU/SO should have been the best approach, even though this would have required an hardly achievable sample size. In conclusion, we are still at the starting point. Looking for new data able to clearly differentiate the TKIs, and the right sequence of administration. Currently we can only try to tailor treatment with TKIs according to the single patient profile. Therefore, we believe the “way to Tipperary” is still a long way.