Cell death as a phenomenon in embryonic development was first described over 100 years ago. Approximately 30 years ago the process was named apoptosis, and its involvement is now recognized in many life processes, in virtually every animal species, and from fertilization to the death of an organism. In cardiovascular development, it coincides with major developmental processes in specific time windows. Both intrinsic (controlled by mitochondrial activity) and extrinsic (starting with death receptors) apoptotic pathways co-regulate developmental mechanisms. During cardiac development, many cell populations are recruited to the heart, where they differentiate into cardiomyocytes, fibroblasts, smooth muscle cells, endocardial and endothelial cells lining the inner surfaces, and epicardial cells lining the outer contours. In particular, neural crest-derived cell populations, which migrate to specific locations in the heart, are prone to apoptosis. During the complex geometric changes that occur in the primary heart tube and connected vessel segments, proper interaction of the respective cell populations guarantees the ensuing steps of differentiation. Growth factors, including endothelin, VEGF, and TGF-β, as well as other factors, such as FasL, play dominant roles in these phases. Transgenic and knockout studies have provided strong evidence for aberrant patterns of apoptosis resulting in congenital malformations and syndromic malformations, including septation anomalies, interrupted aortic arch segments, coronary anomalies, and DiGeorge syndrome. Embryonic remodeling of the arterial system, including the coronary arteries, is accompanied by apoptosis patterns, the disruption of which results in severe malformations. It is interesting to note that hemodynamic factors, such as flow-driven shear stress, regulate the expression of genes that are important for signaling molecules such as endothelin and NO-synthase. In general, high shear stress protects against apoptosis, thus preventing the onset of disease processes in the fully-grown vasculature, and regulating the remodeling of the vascular system in the embryo. Birth Defects Research (Part C) 75:305–313, 2005. © 2006 Wiley-Liss, Inc.