New concepts in the field of atherothrombosis include the human potential to repair and regenerate areas of vascular damage through endogenous growth factors, and the identification of uncommon arterial thrombophilias that promote atherothrombosis. The endogenous factors erythropoietin and insulin-like growth factor-1 are emerging as robust opponents of the vascular and hemostatic alterations that occur in atherothrombosis. Both factors activate the intracellular Akt pathway and the biosynthesis of constitutive nitric oxide, with anti-apoptotic, insulin-sensitizing, vasodilator, anti-inflammatory, antioxidant and antiplatelet effects, all of which oppose arterial degeneration and occlusion. Additionally, erythropoietin and insulin-like growth factor-1 induce the mobilization of stem cells that can differentiate and repair areas of vascular damage thereby halting the progression towards established disease. In selected patients with an arterial thrombotic event, we believe it is justified to search for an uncommon acquired or inherited thrombophilic condition in the presence of at least one of the following: young age, recurrent events, lack of traditional metabolic or acquired vascular risk factors, and no significant artery stenoses at angiography. In these groups of patients, and in those with a marked family history of thrombosis, the prevalence of several functional polymorphisms of genes involved in the hemostatic system is significantly higher compared with controls. Acquired thrombophilias that should be searched for include the antiphospholipid syndrome, systemic lupus erythematosus, and myeloproliferative disorders.