Over the last 20 years I have worked on drug development, optimizing anticancer therapies by understanding the synergy and antagonism of drugs when conventional anticancer drugs with are combined with molecular targeted agents, and on mechanisms of drug resistance. Identification of cancer stem cells has been useful in defining a subpopulation of cells responsible for drug resistance and tumor recurrence. However, in order to develop more effective therapies for cancer, we need a better understanding of stem cell biology. We recently came to appreciate that the accessibility of transcription factors (TFs) to DNA ultimately controls stemness, reprogramming and differentiation. The Laboratory of Receptor Biology and Gene Expression (LRBGE) under the direction of Gordon Hager pioneered the study of changes in the global unbiased chromatin landscape (i.e., all sites in the genome that are accessible to interaction with proteins at any time) in response to activation of glucocorticoids and other nuclear receptors. In-depth bioinformatic annotation to the mammalian genome provides an unbiased view of changes in accessibility for all regulatory elements in any cell type at any given time. These studies provide information that is not possible to obtain by other techniques, such as ChIP. We are using DHS-seq to probe chromatin modifications in iPS and mesenchymal stem cells differentiated to osteogenic lineage, a process that requires glucocorticoids. These studies have led to an appreciation of novel pathways involved in stem cell differentiation and osteogenesis. We have also uncovered novel pathways involved in metastatic progression and acquisition of drug resistance. Our current studies involve development of a bioinformatic method that allow linking the novel information on global changes in Dnase hypersensitivity to miRNA, gene expression and other cancer genome data.