Physiological angiogenesis refers to a naturally occurring process of blood vessel growth and regression, and it occurs as an integral component of tissue repair and regeneration. During wound healing, sprouting and branching results in an extensive yet immature and leaky neovascular network that ultimately resolves by systematic pruning of extraneous vessels to yield a stable, well-perfused vascular network ideally suited to maintain tissue homeostasis. While the molecular mechanisms of blood vessel growth have been explored in numerous cell and animal models in remarkable detail, the endogenous factors that prevent further angiogenesis and control vessel regression have not received much attention and are largely unknown. In this review, we introduce the relevant literature from various disciplines to fill the gaps in the current limited understanding of the major molecular and biomechanical inducers of vascular regression. The processes are described in the context of endothelial cell biology during wound healing: hypoxia-driven activation and sprouting followed by apoptosis or maturation of cells comprising the vasculature. We discuss and integrate the likely roles of a variety of endogenous factors, including oxygen availability, vessel perfusion and shear stress, intracellular negative feedback mechanisms (Spry2, vasohibin), soluble cytokines (CXCL10), matrix-binding proteins (TSP, PEDF), protein cleavage products (angiostatin, vasostatin), matrix-derived anti-angiogenic peptides (endostatin, arresten, canstatin, tumstatin), and the biomechanical properties of remodeling the extra-cellular matrix itself. These factors aid in the spatio-temporal control of blood vessel pruning by inducing specific anti-angiogenic signaling pathways in activated endothelial cells, pathways which compete with pro-angiogenic and maturation signals in the resolving wound. Gaining more insight into these mechanisms is bound to shed light on unresolved questions regarding scar formation, tissue regeneration, and increase our understanding of the many diseases with angiogenic phenotypes, especially cancer.