The septal perforating arteries of the heart usually branch off from the anterior and inferior interventricular arteries and supply the interventricular septum and the conduction system therein. Since the septal perforating arteries are not directly visible from the outside of the heart, their anatomy and variations might be overlooked. However, the septal perforating arteries have their unique anatomy that needs to be recognized to avoid the damage of the vessels especially during common cardiac procedures such as the coronary artery bypass graft, percutaneous coronary intervention, and aortic valve replacement. A better understanding of these important arteries will help physicians to enhance the overall cardiac care for their patients. Therefore, this article discusses the anatomy, the relationship to the conduction system of the heart and the clinical significance of the septal perforating arteries.