The most severe stages of arteriopathy often involve multifocal macrovascular lesions leading to defective perfusion of the distal tissues and subsequent dysfunction of the microcirculation. Diabetic autonomous neuropathy facilitates and aggravates this endothelial dysfunction. Loss of vasomotricity, platelet and white cell activation, and cytokine release lead to an obstruction of the capillaries and alteration or even destruction of the endothelium. At this stage, the lesions are irreversible and tissue vitality is definitively compromised. The goal of medical treatment is to delay the development of dysfunction and subsequent destruction of the microcirculation before, during and after restoration of sufficient flow through the macrocirculation lesions by angioplasty and/or surgery. Extrapolating from in vitro and animal studies, two mediators, EDRF (NO) and prostacycline, could theoretically inactivate inappropriate activated cells and re-establish flow. Besides their vasodilator proprieties, NO and prostacycline have a synergetic inhibitory effect on platelet and leukocyte activation. The role of platelet antiaggregates and heparins in this stage of severe chronic ischemia remains to be determined. The relative failures of therapeutic drug trials conducted since the end of the eighties demonstrates the importance of intervening before the microcirulation disorders become too severe. Until new compounds are developed, therapeutic progress can be achieved by more precise and earlier detection of alterations in the microcirculation to enable optimal management of arteriopathy of the lower limbs with surgery or angioplasty.