The population of patients with advanced coronary artery disease (CAD) is growing as a result of the aging of the general population, the extensive use of revascularization, and the efficacy of therapies that have prolonged the survival of patients with severe atherosclerosis. Patients with symptomatic CAD survive to a point where little else can be done to relieve their angina. Despite an anticipated growth in the number of patients with this condition within the next few decades, advanced CAD receives relatively little attention by the medical and research communities. As a result, the scope of the disease is not well defined, its coverage in guidelines from professional associations is limited, and few new medical options are available. In response to this, a group of experts from different fields were brought together at a meeting held December 4 to 5, 2006. This document has been developed as a 2-part article. In the first part, the contemporary and emerging therapies for advanced CAD were reviewed. The present part reviews the current status of understanding of advanced CAD, the limits of contemporary therapies, and the difficulties in and barriers to the development of new treatments.