Collateral blood vessels are unique, naturally occurring endogenous bypass vessels that provide alternative pathways for oxygen delivery in obstructive arterial conditions and diseases. Surprisingly however, the capacity of the collateral circulation to provide protection varies greatly among individuals, resulting in a significant fraction having poor collateral circulation in their tissues. We recently reviewed evidence that the presence of naturally-occurring polymorphisms in genes that determine the number and diameter of collaterals that form during development (ie, genetic background), is a major contributor to this variation. The purpose of this review is to summarize current understanding of the other determinants of collateral blood flow, drawing on both animal and human studies. These include the level of smooth muscle tone in collaterals, hemodynamic forces, how collaterals form during development (collaterogenesis),