Fibroblasts are central to the acute and chronic response of tissues to stress: they are necessary for wound healing, involved in inflammatory responses and critical for long term remodeling of tissue. These diverse roles of fibroblasts arise from the cells' ability to respond to internal and extracellular cues regarding the physical state of the host tissue. In this article, we review recent evidence for the role of chromatin as a sensor of cellular stress and chromatin-dependent gene regulatory events that may be essential for fibroblast activation in the setting of injury. This emerging evidence highlights chromatin structure and accessibility as features necessary for our understanding of how cell type-specific epigenomes sense and respond to stress.