An unstable lesion may rupture and cause an acute thrombotic reaction. These lesions contain a large lipid pool covered by a thin fibrous cap. The stress in the cap increased with decreasing thickness and increasing macrophage infiltration. Intravascular ultrasound (IVUS) elastography might be an ideal technique to assess the presence of lipid pools and identify high stress regions. Elastography assesses the local mechanical properties of tissue using its deformation caused by the intraluminal pressure. The technique was validated in vitro using diseased human coronary and femoral arteries. These experiments demonstrated that the strain in the three plaque types is different (P < 0.001). Especially between fibrous and fatty tissue, a highly significant difference (P = 0.0012) was found. Additionally, the predictive value for identifying the vulnerable plaque was investigated. A high strain region at the lumen vessel wall boundary has 88\% sensitivity and 89\% specificity for identifying these plaques. In vivo, the technique is validated in an atherosclerotic Yucatan mini-pig animal model. This study also revealed higher strain values in fatty than fibrous plaques (P < 0.001). The presence of a high strain region at the lumen plaque interface has a high predictive value for identifying macrophages. Patient studies revealed high strain values (1-2\%) in soft plaques. Calcified material shows low strain values (0-0.2\%). With the development of three-dimensional elastography, identification of weak spots over the full length of a coronary artery becomes possible. In conclusion, intravascular elastography is a unique tool to assess lesion composition and vulnerability. The development of three-dimensional elastography provides a technique that may develop into a clinical available tool for identifying the rupture-prone plaque.