Ischemic heart disease (IHD) is caused by the narrowing of arteries that work to provide blood, nutrients, and oxygen to the myocardial tissue. The worldwide epidemic of IHD urgently requires innovative treatments despite the significant advances in medical, interventional, and surgical therapies for this disease. Angiogenesis is a physiological and pathophysiological process that initiates vascular growth from pre-existing blood vessels in response to a lack of oxygen. This process occurs naturally over time and has encouraged researchers and clinicians to investigate the outcomes of accelerating or enhancing this angiogenic response as an alternative IHD therapy. Therapeutic angiogenesis has been shown to revascularize ischemic heart tissue, reduce the progression of tissue infarction, and evade the need for invasive surgical procedures or tissue/organ transplants. Several approaches, including the use of proteins, genes, stem/progenitor cells, and various combinations, have been employed to promote angiogenesis. While clinical trials for these approaches are ongoing, microvesicles and exosomes have recently been investigated as a cell-free approach to stimulate angiogenesis and may circumvent limitations of using viable cells. This review summarizes the approaches to accomplish therapeutic angiogenesis for IHD by highlighting the advances and challenges that addresses the applicability of a potential pro-angiogenic medicine.