Genomics has revolutionized and personalized our approach to cancer therapy, with clinical trials now frequently involving patient stratification based on tumor genotype. Rational drug design specifically targeting the most common genetic events and aberrantly regulated pathways in human cancers makes this approach possible. However, our understanding of the wiring of oncogenic signaling networks and the key downstream effectors driving human cancers is incomplete, limiting our ability to predict clinical responses or identify mechanisms of resistance to targeted therapeutics. Recent studies in independent cancer lineages driven by distinct oncogenic signaling events point to a common downstream target, the mammalian (or mechanistic) target of rapamycin complex 1 (mTORC1), which dictates the cellular and clinical response to pathway-specific inhibitors. mTORC1 is a highly integrated signaling node that promotes anabolic cell growth and proliferation and lies downstream of multiple oncogenes and tumor suppressors, including those influencing the PI3K-Akt and RAS-RAF-MEK-ERK pathways. Studies are now suggesting that to effectively target the major oncogenic signaling pathway in a given tumor, mTORC1 must be inhibited, and that its sustained activation is a major mechanism of resistance to such targeted therapies.