Activation of hepatic stellate cells (HSC) to a myofibroblast-like phenotype is the pivotal event in liver fibrosis. In uninjured liver, HSC are quiescent and non-dividing, but upon liver injury these cells undergo a dramatic change in phenotype which generates activated myofibroblast-like HSC. The change in phenotype is underpinned by a global change in gene expression with hundreds of genes being up- or downregulated. Molecular events that orchestrate changes in gene expression take place at the level of chromatin packaging which is altered through three main processes: histone modifications, DNA methylation, and silencing by non-coding RNAs. The present review focuses on the epigenetic regulation of HSC activation.