Cardiovascular disease is the number one cause of mortality in the United States. Atherosclerosis, the primary etiology of cardiovascular disease is hypothesized to be a time-dependent response to arterial injury. Although risk factors for atherosclerosis are systemic in nature, certain arteries (e.g., coronary arteries) are more susceptible to plaque formation than others. The heterogeneous distribution of atherosclerosis in the vasculature is thought to be related to biomechanical factors. A review of the relevant pathological features of atherogenesis and how physiologically-consistent mechanical stimuli can impact those processes supports this notion. However, specific investigations geared toward finding the mechanistic link between mechanical stimuli and early atherogenic processes are required to differentiate those stimuli that facilitate and those that inhibit atherogenesis. Such knowledge is required for intelligent direction in the search for potential targets for clinical intervention.