Investigations into physiologically controlled capillary regression report the provocative finding that microvessel regression occurs in the face of persistent elevation of skeletal muscle VEGF expression. TSP‐1, a negative angiogenic regulator, is increasingly being observed to temporally correlate with capillary regression, suggesting that increased TSP‐1 (and not reduction in VEGF per se) is needed to initiate, and likely regulate, capillary regression. Based on evidence being gleaned from physiologically mediated regression of capillaries, it needs to be recognized that capillary regression (and perhaps capillary rarefaction with disease) is not simply the reversal of factors used to stimulate angiogenesis. Rather, the conceptual understanding that angiogenesis and capillary regression each have specific and unique requirements that are biologically constrained to opposite sides of the balance between positive and negative angioregulatory factors may shed light on why anti‐VEGF therapies have not lived up to the promise in reversing angiogenesis and providing the cure that many had hoped toward fighting cancer. Emerging evidence from physiological controlled angiogenesis suggest that cases involving excessive or uncontrolled capillary expansion may be best treated by therapies designed to increase expression of negative angiogenic regulators, whereas those involving capillary rarefaction may benefit from inhibiting negative regulators (like TSP‐1).