Insights into the niche-environment within IH that regulates this primitive endothelium including the vascular endothelial growth factor (VEGF) system, the insulin-like growth factor (IGF) system, the TRAIL-osteoprotegerin (OPG) anti-apoptotic pathway, and the renin–angiotensin system (RAS), provide clues into the post-natal environment that modulates the programed biologic behavior of IH and underscores current and future novel therapies. The gene discussed is TNFRSF11B; the disease is isolated hemihyperplasia.