Cancer is a genetic disease but epigenetic processes also contribute to cancer development and progression. Epigenetic processes include molecular pathways that modify the DNA itself or the proteins that are associated with DNA (i.e. histones), thereby affecting how the genetic information is used to maintain cellular states. Cancer cells exploit the normal epigenetic processes to their advantage to support uncontrolled growth and evade host defense mechanisms. Our proposal aims to understand the epigenetic requirements for cancer initiation and progression and how they can be used to develop prognostic assays that can predict cancer clinical outcome or response to therapeutics. We have made significant progress in all of our aims. We are discovering new basic principles governing epigenetic processes in human embryonic stem cells versus more differentiated cell types and understanding how these principles are implemented and regulated by the different types of cells. We have also shown that epigenetics can be used for cancer prognostic purposes as well as for prediction of response to specific cancer chemotherapeutics.