In response to DNA double-stranded breaks (DSBs) cells activate a signaling cascade known as the DNA damage response (DDR) whose main function is to promote the repair of the lesions while it delays cell cycle progression until repair is completed. Whereas most cells respond alike to an equivalent dose of DNA damage, certain degree of heterogeneity exists in the strength of the DDR that is assembled in each individual cell. This variability might be accounted for by erratic changes that aggregate into the inherent noise of biological systems. However, we have recently found that the overall degree of chromatin compaction impinges a direct constrain on the activation of the DDR, providing a simple chromatin-based model to explain the cell-to-cell variability observed in cell populations. We here provide an overview of the available data, including our own, that would be supportive of such a model and discuss how this perspective might be used to explain previous observations.