Signaling involves the coordinated action of multiple molecules including stimuli, receptors and enzymes part of which interact with the transcriptional machinery and target chromatin. Signaling systems regulate the cell events responsible for survival, development and homeostasis. Many of the signaling pathways induce target gene activation through interaction with the transcription machinery, including RNA polymerase II, and with histone modifying complexes. These studies are having a broad impact on chromatin biology. Recent studies suggest that chromatin itself receives the signals. Increasing examples are illustrating novel regulatory mechanisms that promote our understanding of development and disease.