AbstractChromatin immunoprecipitation (ChIP), when paired with sequencing or arrays, has become a method of choice for the unbiased identification of genomic‐binding sites for transcription factors and epigenetic marks in various model systems. The data generated is often then interpreted by groups seeking to link these binding sites to the expression of adjacent or distal genes, and more broadly to the evolution of species, cell fate/differentiation or even cancer development. Against this backdrop is an ongoing debate over the relative importance DNA sequence versus chromatin structure and modification in the regulation of gene expression (Anon. 2008a Nature 454: 795; Anon. 2008b Nature 454: 711–715; Henikoff et al. 2008 Science 322: 853; Madhani et al. 2008 Science 322: 43–44). Rationally there is a synergy between the two and the goal of a biologist is to characterise both comprehensively enough to explain a cellular phenotype or a developmental process. If this is truly our goal then the critical factor in good science is an awareness of the constraints and potential of the biological models used. The reality however is often that this discussion is polarised by funding imperatives and the need to align to a transcription factor or epigenetic camp. This article will discuss the extrapolations involved in using ChIP data to draw conclusions about these themes and the discoveries that have resulted. J. Cell. Biochem. 107: 19–29, 2009. © 2009 Wiley‐Liss, Inc.