Signal transduction pathways alter the gene expression program in response to extracellular or intracellular cues. Mitogen-activated protein kinases (MAPKs) govern numerous cellular processes including cell growth, stress response, apoptosis, and differentiation. In the past decade, MAPKs have been shown to regulate the transcription machinery and associate with chromatin-modifying complexes. Moreover, recent studies demonstrate that several MAPKs bind directly to chromatin at target genes. This review highlights the recent discoveries of MAPK signaling in regard to histone modifications and chromatin regulation. Evidence suggesting that further unknown mechanisms integrate signal transduction with chromatin biology is discussed.