Shear stress of the blood at the vessel wall plays an important role in many processes in the cardiovascular system primarily focused on the regulation of vessel lumen and wall dimensions. Over the years, we studied the role of shear stress in the initiation, progression and destabilization of vulnerable plaques in human coronary and carotid arteries. Plaque rupture, however, occurs when wall stress exceed the local plaque strength. Plaque strength largely depends on the blood pressure and the local plaque composition which is also regulated by the local shear stress. In this seminar, an overview will be given on studies performed and techniques that were developed to unravel the complex interplay between biomechanics, vascular biology and cardiovascular disease.