There is now an abundance of evidence to support the proposition that perinatal growth influences have long term impact on defining adult health status – cardiovascular health in particular. These investigations have highlighted the role that tissue modeling processes enacted in the early postnatal period play in setting the scene to ensure long term appropriate growth responses. Although the phenomenology of early disease ‘origins’ is generally accepted, understanding of the mechanisms involved is limited. The emphasis has been primarily on aspects of the gestational environment which influence fetal growth – ie nutritional state and other factors associated with uteroplacental insufficiency. Less is understood about how offspring genetic/epigenetic factors can operate independently during the perinatal period to define subsequent tissue and organ growth. The switch from proliferative (ie mitotic) to hypertrophic cellular growth occurs in the perinatal period as myocytes exit from the cell cycle, and beyond this period the myocardium is considered to be largely a terminally differentiated tissue. Thus, the myocyte population is essentially fixed at this time point, defining the non-replaceable pool of cells available to support ongoing maturational growth of the heart. As a highly metabolically active tissue, the heart is particularly vulnerable to substrate ‘starvation’ stress in the perinatal period, during transition from placental to lactational nutrition. To support energy homeostasis, autophagic activity is upregulated in multiple tissues during the neonatal starvation period – and particularly in the heart. A high level of autophagic activity can be lethal, and cell death by autophagy is recognized as a distinctive, non-apoptotic type of programmed cell death. Thus, myocyte loss through autophagy during the perinatal period has the potential to significantly deplete the heart cell population. Recently, using novel experimental animal models, it has been possible to demonstrate a link between reduced cardiac myocyte population in the neonatal heart due to upregulated autophagy and abnormal cardiac enlargement in the adult. An interaction between angiotensin II/G-protein-coupled-receptor and IGF1/PI3Kinase-dependent signaling pathways is implicated in this neonatal growth suppression and autophagy induction. Furthermore there is emerging evidence that autophagy pre-disposition and the cross-talk between these signalling pathways is different in male and female hearts, and new findings that microRNA molecules (miR) are the key to sex-specific programming patterns of gene expression which have long-term tissue modeling influence on cardiac pathophysiology. Understanding the early epigenetics of disease predisposition has become an exciting and high priority research pursuit which will yeild important information about the mechanisms of sex difference in adult cardiac disease outcomes.