Atherosclerosis is characterized by chronic inflammation and enrichment of inflammatory cells in the vessel wall. Acute inflammation can lead to damaged endothelium triggering the coagulation cascade and thrombus formation. Likewise, the clotting cascade may elicit an inflammatory response. The vascular endothelium regulates vascular tone, permeability, inflammation, thrombosis, and coagulation. Dysfunction of the vascular endothelium can promote atherosclerotic disease processes. Prostanoids (prostaglandins, thromboxane, and prostacyclin) have been established as inflammatory mediators in vascular endothelial function and there continues to be growing insights into their role in atherosclerotic disease. This review examines the role of prostanoids as paracrine inflammatory mediators of atherosclerotic vascular disease, highlighting the relevant physiology of eicosanoid production and endothelial dysfunction. We consider the role of prostanoids in systemic diseases associated with high cardiovascular morbidity and mortality, including diabetes mellitus, coronary artery disease, peripheral arterial disease, rheumatologic disorders, and dyslipidemia. We present emerging evidence that cardio-protective and lipid lowering medications, such as irbesartan and simvastatin may exert their effects via prostanoid mediated pathways. Both serum and urinary prostanoids may be utilized as diagnostic predictors of disease; for example 8-iso-PGF2α in the serum has recently been reported as an independent predictor of symptomatic peripheral arterial disease. In addition, we discuss current recommendations on established therapeutic uses of prostanoids for atherosclerotic diseases, such as the use of PGE1 for the treatment of peripheral arterial disease. Finally, we investigate original therapeutic modalities of various prostanoids involved in the aforementioned diseases.