Refractory angina pectoris constitutes a manifestation of severe ischemic heart disease that cannot be treated adequately either with conventional medication or with interventional techniques including percutaneous coronary angioplasty (PTCA). As a result, new therapeutic strategies, aiming on angiogenesis, were evolved in order to improve functional class and health related quality of life (HRQOL) indices. Among them, gene therapy constitutes a very promising alternative treatment for these patients. In this review, we will describe i) the definition of refractory angina ii) pathophysiology of angiogenesis, iii) routine as well as novel imaging techniques of neovascularization and iv) current treatment options for refractory angina. Secondly we will review the main angiogenic clinical trials, which will also be commented regarding their effectiveness to reduce the recurrency of angina symptoms and improve health-related quality-of-life, as well as the functional class of patients with chronic ischemic disease.