The results achieved with targeted therapy have changed the natural course of kidney cancer not amenable to local therapy. Sunitinib, bevacizumab and pazopanib are approved in the first-line setting for patients at good/intermediate prognosis, while temsirolimus should be the first-line agent to be used in patients at poor prognosis. The oncology community has been eagerly awaiting results as far as second-line treatment is concerned. The RECORD-1 and AXIS trials provided evidence in favor of everolimus and axitinib, respectively, in patients pretreated with VEGF-directed agents. As the number of available agents grows, so does the possibility of using multiple lines of therapy with a potential benefit in overall survival. The third-line setting has been poorly investigated, and no comparative prospective trials are presently available. Retreatment with VEGF-directed therapy may be an option in everolimus-pretreated patients, with the possibility that mTOR inhibitors may reverse resistance to VEGF-directed therapy. Grunwald et al. presented retrospective data showing that retreatment with VEGF-directed targeted agents, including sunitinib, bevacizumab/interferon, dovitinib and sorafenib, was associated with a progression-free survival time of approximately 5 months. Although the evidence provided by retrospective studies is weak, their role in highlighting matters of clinical relevance deserving investigation is undoubtful, as demonstrated by the retrospective study discussed in this paper.