Long interspersed nuclear elements (LINEs) are mobile sequences shown to play a fundamental role in eukaryotic genome evolution. Recently, increasing interest has been directed at unveiling molecular mechanisms by which LINE-1 (L1), a ubiquitous member of this family, regulates gene expression and mammalian cell development, differentiation, and cancer. This mini review summarizes recent studies conducted to examine stress-induced L1 reactivation, with special attention given to the role of E2F/Rb transcription factors in epigenetic silencing of L1 and its potential role as a global modifier of chromatin structure and function. The last section focuses on the impact of histone deacetylase inhibitors in the regulation of gene function, chromatin structure, and cancer treatment through alterations in epigenetic signaling.