One of the key challenges facing biomedical research is to extract biologically meaningful information from the ever-increasing scale and complexity of datasets generated through high-throughput approaches. Hematopoiesis represents one of the most experimentally tractable mammalian organ systems and, therefore, has historically tended to be at the forefront of applying new technologies within biomedical research. The combination of massive parallel sequencing technologies with chromatin-immunoprecipitation (ChIP-Seq) permits genome-scale characterization of histone modification status and identification of the complete set of binding sites for transcription factors. Because transcription factors have long been recognized as essential regulators of cell fate choice in hematopoiesis, ChIP-Seq technology has rapidly entered the arena of modern experimental hematology. Here we review the biological insights gained from ChIP-Seq studies performed in the hematopoietic system since the earliest studies just 4 years ago. A surprisingly large number of different approaches have already been implemented to extract new biological knowledge from ChIP-Seq datasets. By focusing on successful insights from multiple different approaches, we hope to provide stimulating reading for anyone wanting to utilize ChIP-Seq technology within their particular research field. Copyright © 2011 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.