Arterial occlusive diseases are a major cause of morbidity and death in the United States. The enlargement of pre-existing vessels, which bypass the site of arterial occlusion, provide a natural way for the body to compensate for such obstructions. Individuals differ in their capacity to develop collateral vessels. In recent years much attention has been focused upon therapy to promote collateral development, primarily using individual growth factors. Such studies have had mixed results. Persistent controversies exist regarding the initiating stimuli, the processes involved in enlargement, the specific vessels that should be targeted, and the most appropriate terminology. Consequently, it is now recognized that more research is needed to extend our knowledge of the complex process of collateral growth. This basic science review addresses five questions essential in understanding current problems in collateral growth research and the development of therapeutic interventions.