Eukaryotic cells store their genetic information in the form of a highly organized nucleoprotein complex termed chromatin. The high degree of compaction of DNA within chromatin places severe constraints on proteins that require access to the DNA template to facilitate gene transcription, DNA replication, and DNA repair. As a consequence, eukaryotic cells have developed sophisticated mechanisms to allow chromatin to be rapidly decompacted locally for access by DNA-binding proteins. Once thought to play only a structural role, it now appears that chromatin plays a key regulatory role by marshalling access to the DNA template. We have reviewed the role played by chromatin in the cellular response to physiological and toxicological stimuli and described how changes in chromatin structure may in the future be used as markers of toxicity. We also review the evidence that chromatin itself is the direct target of certain toxicants and that toxicant-induced perturbations in chromatin structure may precipitate adverse effects.