The application of mathematical modelling to chromatin-mediatedgene regulation is gaining momentum, but is stillsurprisingly rare. Here we review examples in which thecombination of quantitative experimentation and mathematicalmodelling has given mechanistic insights into the processesinvolved. Examples include recruitment of epigenetic regulators,the establishment and maintenance of epigeneticmemory, the dynamic cell cycle – dependent changes inchromatin binding of epigenetic regulators, and the contributionof 3D genome architecture to cell identity. The successfulcombination of theory and experiment requires tractableexperimental systems in which quantitative measurements andprecise perturbations are possible. The advent of single celltechnologies and genome editing presents an unprecedentedopportunity for combining quantitative experiments, preciseperturbation and modelling, that in future will enable newepigenetic data to be embedded in a coherent theoreticalframework.