The movement toward precision medicine with targeted therapeutics for cancer treatment has been hindered by both innate and acquired resistance. Understanding the molecular wiring and plasticity of oncogenic signaling networks is essential for the development of therapeutic strategies to avoid or overcome resistance. The mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) represents a highly integrated signaling node that is dysregulated in the majority of human cancers. Several studies have revealed that sustained mTORC1 inhibition is essential to avoid resistance to therapeutics targeted against the driving oncogenic pathway in a given cancer. We discuss the role of mTORC1 in dictating the response of tumors to targeted therapeutics and review recent examples from lung cancer, breast cancer, and melanoma.