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Introduction: mTOR and its effectors are central regulators of cellular metabolism in malignant cells and control mRNA translation that ultimately leads to generation of mitogenic proteins. Efforts to target this pathway have been ongoing for over a decade and have had a substantial impact in the management of certain patients with solid tumors. Although activity of mTOR inhibitors has been established in several trials, inability to predict responses remains a limiting factor for the successful incorporation of these agents in the treatment of a variety of malignancies., Areas Covered: Recent clinical findings are discussed and studies focused on advanced phase development of mTOR inhibitors are summarized. The emergence of precision medicine approaches and the effects that such approaches may have on prospective selection of patients for treatment with mTOR inhibitors are discussed. Also, potential approaches and future prospects to improve responses to mTOR inhibitors by modulating other parallel mitogenic pathways essential for malignant cell proliferation are discussed., Expert Opinion: Selective targeting of the mTOR pathway offers significant clinical advantage in subsets of patients with diverse malignancies. Approaches to enhance responses by concomitant targeting of resistance pathways and/or predict responses via identification of molecular markers should substantially impact this area in the near and distant future.