Mutations and epimutations interact reciprocally to drive unrestrained growth and malignant progression of cancer. Specific genetic mutations of epigenetic regulators may cause widespread epigenetic alterations, and epimutations similarly predispose to genetic alterations either locally or across the genome. This GRC series focuses on the discovery and function of novel recurrent genetic and epigenetic alterations, the mechanisms that predispose to them, and their functional consequence on tumor cell behavior, therapeutic response and numerous cancer phenotypes. More comprehensive and integrative analysis of cancers has been enabled and significantly advanced by genomic technologies. Such profiling and analyses are now possible on impressively small amounts of tissue or potentially on single cells, allowing heterogeneity to be addressed at the regional and cellular level. From the discovery of the alterations, along with significant structural biology and chemistry, new agents with therapeutic potential have arisen. The translational value of these discoveries and promising therapeutic agents is being put to the test internationally in preclinical and clinical settings, and will be discussed in depth. Personalized genetic and epigenetic therapies for cancer patients are being taken to a new level. Sessions in this meeting will focus on distinguishing driver from passenger mutations and epimutations, the mechanistic links between genetic mutations and epimutations, and the identification of actionable defects in primary cancers. Novel therapies that target specific genetic alterations or aim to reverse epigenetic alterations more globally will be discussed by leaders from academic and industry laboratories.