Blood and vascular disorders underlie a plethora of pathologic conditions and are the single most frequent cause of human disease. Ischemia, involving restricted blood flow to tissues is the most common consequence of vessel dysfunction resulting in the disruption of oxygen and nutrient delivery and the accumulation of waste metabolites. Cells cannot survive extended severe ischemia but may be able to adapt to a moderate condition where diffusion to and from bordering nonischemic regions sustains vital functions. Under this condition, the secondary functions of effected cells are likely to be impaired, and a new metabolic equilibrium is established, determined by the level of cross-diffusion and degree of hypoxia. In tissues with a normally high metabolic turnover such as skeletal and cardiac muscle, even mild ischemia causes hypoxia, acidosis, and depressed function (contractility) and eventually threatens myocyte viability and organ function. Ischemic cardiac muscle is additionally vulnerable because reperfusion is essential for survival but reperfusion itself poses additional stress principally from increased production of free radicals during reoxygenation. The latter effect is called reperfusion injury and can cause as much damage as the ischemia. The treatment possibilities for ischemia-related vascular disease are limited. Lipid/cholesterol-lowering agents, diet and antiplatelet adherence (aspirin) therapy may help slow the progression of vessel disease in some instances; but surgical reconstruction may be the only option in advanced stages, and even this is not always an option. An alternative and rather obvious strategy to treat ischemia is to activate endogenous angiogenic or arteriogenic pathways to stimulate revascularization of the tissue. The feasibility of such a strategy has now been established through the results of studies over the past decade, and a new discipline called therapeutic angiogenesis has emerged. This review focuses on the application of therapeutic angiogenesis for treating ischemic muscle disease and includes a critical evaluation of the parameters and limitations of current procedures. The development of this technology has benefited from its application to both peripheral and coronary artery disease and results from both are reviewed here.