Everolimus is an oral derivative of rapamycin which acts as a signal transduction inhibitor. It targets the mammalian target of rapamycin (mTOR), a key serine/threonine kinase regulating cell growth and angiogenesis. Everolimus has been approved for the treatment of pancreatic neuroendocrine tumors (pNETs), metastatic renal cell carcinoma (mRCC), and breast carcinoma. The activity of everolimus was demonstrated in three phase III randomized placebo-controlled trials, RADIANT-3, RECORD 1 and BOLERO 2, in patients with pNETs, mRCC and breast carcinoma, respectively. All three trials reported a statistically significant increase in median progression-free survival, the primary endpoint of the studies, in favor of everolimus. The absence of an overall survival benefit could be related to the cross-over design and subsequent therapies. The focus of our paper is on the best timing to start treatment with everolimus, while additional questions concern the opportuneness of intermittent use of everolimus specifically in long-responding patients. Lastly, we suggest this treatment could be optimized on the basis of patient and disease characteristics.