While it is crucial to recognize that atherosclerosis is the most common etiology for lower extremity ischemia, it is important to know the non-atherosclerotic causes of limb ischemia. Since these pathologies are not as prevalent as atherosclerosis, knowledge about these entities helps make a broad differential diagnosis at the initial clinical evaluation. This chapter includes the following non-atherosclerotic cause of limb ischemia: vasculitis, Takayasu’s arteritis, femoral and popliteal artery aneurysms, external iliac artery endofibrosis, cystic adventitial disease, popliteal artery entrapment, persistent sciatic artery, mid-aortic syndrome, thromboangiitis obliterans (Buerger’s disease), Raynaud’s syndrome, calciphylaxis, warfarin-induced skin necrosis, heparin-induced skin necrosis, atheroembolic episodes, radiation, brown recluse spider bite, Ehlers-Danlos syndrome, pseudoxanthoma elasticum, ergot derivatives, and neurogenic claudication.