Shear stress and cyclic stretch are mechanical forces on the vessel wall exerted by blood flow and luminal pressure. These forces regulate gene expression and function in vascular cells, including endothelial cells (ECs) and smooth muscle cells (SMCs), thus affecting vascular biology in health and pathobiology in disease. Epigenetics refers to the study of sequence-independent heritable DNA alterations that modulate gene expression, including DNA methylation, histone modification/chromatin remodeling, and RNA-based mechanisms. Recently, the roles of mechanical force-induced epigenetic modifications in vascular gene expression and function have been intensively investigated. This chapter presents a critical concept: vascular gene expression can be mechanically modulated without DNA sequence change. By elucidating the relationship between mechanical forces and epigenetic modifications in gene expression, cell proliferation, angiogenesis, migration, and pathological status, this review provides a conceptual framework for understanding how mechanical force-induced epigenetic modifications modulate gene expression and cellular function in vascular biology in health and pathobiology in disease. This review contributes to our knowledge of how the mechanical microenvironment affects epigenetic changes in vascular cells and modulates their functions and behaviors, with the consequent modulation in vascular diseases.