Throughout life, external and the internal environments interact in normal development and tissue homeostasis as well as in onset of disease. Epigenetic modifications occur in response to environmental changes and play a fundamental role in controlling gene expression without modification of the DNA base sequence. Aging, inflammation, drugs, infections and ultraviolet exposure may have profound effects on epigenetic modifications and trigger susceptibility to diseases. Increasing evidence has demonstrated that epigenetic mechanisms play a key role in regulating the physiopathology of the ocular surface. The evaluation of epigenetic factors in ocular disease would lead to further investigation regarding the potential use of therapeutic targets and diagnostic biomarkers. This review examines specific epigenetic and biochemical mechanisms that may occur in the ocular surface microenvironment. Potential correlation between epigenetic factors and targets should be considered in future approaches to prevention and/or treatment of specific ocular surface disorders.