Evidence suggests that monocyte adhesion to endothelial cells as well as excessive proliferation and migration of vascular smooth muscle cells (VSMC) are key events in the development of atherosclerosis and restenosis after balloon angioplasty. These processes are mainly mediated by growth factors, inflammatory cytokines, chemokines and related factors released by various cells in the vessel wall. The mechanisms of action of these factors are however not very clear. These growth factors and cytokines acting on VSMC and endothelial cells can activate phospholipases with the release of lipids such as arachidonic and linoleic acids. These lipids can be further metabolized by several pathways including the lipoxygenase (LO) pathway. These oxidative pathways can lead to the formation of free radicals and lipid peroxides. LO products have been shown to have potent inflammatory, growth, adhesive and chemoattractant effects in cells. They are also associated with oxidant stress and cellular apoptosis. This chapter reviews the role and mechanisms of action of the LO pathway and its products in the pathogenesis of cardiovascular diseases and diabetic vascular complications. The importance of the leukocyte 12/15-LO in the pathology of these disorders is suggested by studies in which the 12/15-LO null mice displayed attenuated atherosclerosis. Activation of the LO pathway along with associated oxidant stress and signaling pathways may be a common mechanism shared by growth factors and cytokines in leading to increased inflammatory and proliferative disorders, including those associated with atherosclerosis, hypertension and related diabetic vascular complications.