The vascular wall is an integrated functional component of the circulatory system that is continually remodeling or develops arteriosclerosis in response to hemodynamic or biomechanical stress. How vascular cells sense and transduce the extracellular mechanical signals into the cell nucleus resulting in quantitative and qualitative changes in gene expression is an interesting and challenging question. Based on recent progress in this field, this article attempts to formulate a biomechanical-stress hypothesis-that physical force initiates signal pathways, especially mitogen-activated protein kinases (MAPKs), leading to vascular cell death and inflammatory response followed by smooth muscle cell proliferation. Thus, mechanical stress, akin to cytokines or growth factors, can effectively activate signal transduction pathways, resulting in morphological and functional changes in vascular cells, which contribute to the development of arteriosclerosis.