The identification of activated hepatic stellate cells and related cell types as key fibrogenic effectors during liver injury has led to intense evaluation of transcriptional events underlying their behavior. While initial studies focused on characterizing interactions between transcription factors and regulatory regions within gene promoters, epigenetic mechanisms have emerged as major determinants of gene activation and repression, in particular histone acetylation and promoter methylation, as well as other complex conditional interactions that underlie global changes in gene expression. Three examples are provided that illustrate how stellate cell activation may be controlled by widely divergent regulatory pathways, including alternative splicing of a growth inhibitory transcription factor (Kruppel-like factor-6), epigenetic regulation of a factor regulating stellate cell survival (nuclear factor kappaB), and regulation of a transcription factor whose expression maintains stellate cell quiescence (LIM homeobox gene 2 [Lhx2]). These complex cascades illustrate how clarifying the finely tuned interdependent layers of transcriptional, translational, post-translational and epigenetic gene regulation in stellate cells is raising new prospects for therapy of hepatic fibrosis.