Mammalian target of rapamycin (mTOR), an important sensor for growth factors, nutritional deprivation and other stresses in controlling translation, plays a critical role in tumorigenesis. Several rapalogs exhibited antitumor activity clinically, with a modest average response rate, while a small subset of patients exhibited significantly greater clinical benefits. A better understanding of cellular mechanisms and the results of clinical studies can help identify an optimal biomarker to predict the efficacy of mTOR inhibitors. We discuss these potential markers in terms of selection of candidates, baseline expression, pathway inhibition and source of targeted protein.