Arterial occlusions do not always lead to death of the dependent tissue because a collateral circulation develops by growth-enlargement of the network of occlusion-spanning arterioles. Structural enlargement reaches dimensions of about 3- to 5- fold of the initial diameter in the peripheral circulation of most mammals and up to 10-fold in the canine heart. Growth is initiated by fluid shear stressed endothelium, adhesion of bone marrow-derived mononuclear cells and matrix digestion by proteinases, which allows structural dilatation. The involvement of the innate immune system (IIS) is suggested by the transient induction of TNF, Toll-like receptors and iNOS and eNOS. The IIS-stimulant LPS is able to stimulate the growth process. Bone marrow derived mononuclear cells, predominantly monocytes and T-cells, play an important role as factories of growth factors and proteinases. NO plays an important role because the process of arteriogenesis can be blocked by L-NAME. Femoral artery ligature in eNOS targeted mice did not interfere with arteriogenesis, but treating eNOS targeted mice with the iNOS inhibitor L-NIL resulted in complete inhibition of collateral artery growth and to necrosis and self-amputation after femoral occlusion. We conclude therefore that iNOS, which belongs to the instruments of defense of the IIS, is the important determinant of the growth of collaterals. Its source are the adhering mononuclear bone marrow derived cells that do not change phenotype into endothelial or smooth muscle cells.