Recent technological developments have revolutionized our understanding of transcriptional regulation by providing an unprecedented ability to interrogate in vivo transcription factor binding. The combination of high-throughput sequencing with chromatin precipitation of transcription factors and specifically labeled histones has allowed direct protein-DNA contacts to be visualized across genomes as large and complex as mammals at base-pair resolution. This chapter reviews the developments that led to these insights, with particular focus on examples of early protein-DNA localization experiments using genomic microarrays in mammals and yeast. Four state-of-the-art research directions are highlighted as examples of previously unimaginable frontiers now under active investigation.