The interaction of a multitude of transcription factors and other chromatin proteins with the genome can influence gene expression and subsequently cell differentiation and function. Thus systematic identification of binding targets of transcription factors is key to unraveling gene regulation networks. The recent development of ChIP‐Seq has revolutionized mapping of DNA–protein interactions. Now protein binding can be mapped in a truly genome‐wide manner with extremely high resolution. This review discusses ChIP‐Seq technology, its possible pitfalls, data analysis and several early applications. J. Cell. Biochem. 107: 11–18, 2009. © 2009 Wiley‐Liss, Inc.