Aortic dissection is an acute cardiovascular disease associated with high mortality and morbidity. Although uncommon, recent studies have shown that the incidence of this catastrophic disease is steadily increasing. Unfortunately, the disease is still not well recognized on clinical presentation due to lack of specific signs and symptoms. As early diagnosis and initial management are critical for survival, we focused on developing a biochemical diagnostic approach for this disease given its meritorious properties in use in the acute clinical situation and additional projected combined use with established imaging modalities. Studies using an assay developed against smooth muscle myosin heavy chain, a protein which is released from the aortic medial smooth muscle cells on insult to the aortic wall, showed promising results for use of this assay in the diagnosis of aortic dissection. The background of this pioneering assay in addition to its clinical use are discussed in this review.