Foot ulcers are a major complication in patients with diabetes mellitus and involve dramatic restrictions to quality of life and also lead to enormous socio-economical loss due to the high amputation rate. The poor and slow wound healing is often aggravated by the frequent comorbidity of foot ulcers with peripheral arterial disease, making the treatment of this condition even more complicated. While the local treatment of foot ulcers is mainly based on mechanical relief and prevention or treatment of infection, improving perfusion of the impaired tissue remains the major challenge in peripheral arterial disease. While focal arterial stenosis is the domain of interventional angioplasty or vascular surgery, patients with critical limb ischemia and lacking options for revascularization have a much worse prognosis, because current treatment options avoiding amputation are scarce. However, based on recent research efforts, there is rising hope for promising and more-effective therapeutic approaches for these patients. Here, we discuss the current improvements of established therapies aimed at an improvement of limb perfusion, as well as the development of novel cutting-edge therapies based on stem-cell technology. The experiences of a 'high-volume center' for treatment of diabetic foot syndrome with a current major amputation rate of 4% are discussed.