A central sensor of the availability of growth factors, nutrients and energy sources, the mammalian target of rapamycin complex 1 (mTORC1) kinase plays a key role in tumor biology. Consequently, mTORC1 inhibitors have been shown to have broad antitumor activity pre-clinically in experimental tumor models as well as clinically in cancer patients. Strikingly, certain tumor types appear to be predisposed to respond to mTORC1 inhibition, a phenomenon related to deregulation of critical elements of the PI3K/mTORC1 pathway. In this review we address optimization of clinical development in the context of mTORC1 inhibitor-induced activation of survival pathways, crosstalk between different signaling modules involved in malignant transformation, definition of rational target combination scenarios and biologically based dosing and patient stratification strategies. Emphasis is given where possible to mTORC1 drug development decisions based on full clinical publications.