The study investigates the relationship between chromatin accessibility and the binding patterns of the glucocorticoid receptor (GR), a ligand-activated transcription factor. Using digital DNaseI analysis and ChIP-seq, the researchers found that up to 95% of *de novo* genomic binding by GR is targeted to pre-existing foci of accessible chromatin. This binding invariably potentiates chromatin accessibility. The cell-selective occupancy patterns of GR appear to be determined by cell-specific differences in baseline chromatin accessibility, with secondary contributions from local sequence features. The results provide a framework for understanding regulatory factor-genome interactions and explain the tissue-selectivity of steroid pharmaceuticals and other agents that interact with the genome. The study also highlights the role of chromatin structure in determining the distribution of regulatory factor binding sites, suggesting that sequential factor occupancy during development and differentiation may be largely pre-specified by the chromatin landscape.The study investigates the relationship between chromatin accessibility and the binding patterns of the glucocorticoid receptor (GR), a ligand-activated transcription factor. Using digital DNaseI analysis and ChIP-seq, the researchers found that up to 95% of *de novo* genomic binding by GR is targeted to pre-existing foci of accessible chromatin. This binding invariably potentiates chromatin accessibility. The cell-selective occupancy patterns of GR appear to be determined by cell-specific differences in baseline chromatin accessibility, with secondary contributions from local sequence features. The results provide a framework for understanding regulatory factor-genome interactions and explain the tissue-selectivity of steroid pharmaceuticals and other agents that interact with the genome. The study also highlights the role of chromatin structure in determining the distribution of regulatory factor binding sites, suggesting that sequential factor occupancy during development and differentiation may be largely pre-specified by the chromatin landscape.