INTRODUCTION Stimulation of coronary collateral vessel growth by therapeutic angiogenesis (TA) offers an alternative treatment option for patients with refractory angina. Several TA modalities, including delivery to the heart of angiogenic growth factors (proteins or genes) and cells have been tested in clinical trials in the past two decades, but so far none of them resulted in significant therapeutic efficacy in large scale studies. This review attempts to identify the main obstacles hindering clinical success and recommends measures to overcome them in the future. AREAS COVERED After stating the medical need and rational for TA, and listing and briefly discussing past and current TA clinical trials, three main areas of obstacles are described: conceptual questions, technical limitations and clinical design uncertainties. Based on scientific and technical advances and lessons learned in past clinical trials, potential solutions to overcome some of these obstacles are proposed. EXPERT OPINION Several success criteria are identified, which apply to any TA approach of choice. It is emphasized, that each of these criteria needs to be met in future clinical trials to have a chance of therapeutic success.