Study of surgical specimens and direct observation by angioscopy has revealed that the varicose venous wall, the valvular annulus, and the valves themselves undergo profound changes. Morphologic investigations have shown dilation of the valve annulus, bulging valve leaflets, commissural dilation, leaflet stretching, and eventually complete destruction of the valves. The venous wall has been seen to undergo changes of thickening in some segments and thinning in others. Our investigations show that inflammation and subsequent remodeling of the venous valves and wall are the fundamental mechanisms underlying the observed lesions. Hemodynamic forces, such as blood pressure changes in the wall and sheer stress, as well as varying planes of laminar and turbulent flow, induce activation of leukocytes and endothelial cells. Integrins appear to act as intermediaries and expression of adhesion molecules has been observed. Breakdown of extracellular matrix of the media and adventitia through activation of matrix metalloproteases (MMP) has been observed. In particular, expressions of MMP-1, MMP-2, MMP-9, and tissue inhibitor of metalloproteinase have been studied. Telangiectasias, reticular veins, and true varicose veins appear to be a consequence of the changes induced by venous hypertension and sheer stress.