Chronic venous disease (CVD) is a debilitating condition with a prevalence between 60-70%. The disease pathophysiology is complex and involves genetic susceptibility and environmental factors, with individuals developing visible telengiectasias, reticular veins, and varicose veins. Patient with significant lower extremity symptoms have pain, dermal irritation, swelling, skin changes, and are at risk of developing debilitating venous ulceration. The signature of CVD is an increase in venous pressure referred to as venous hypertension. The various symptoms presenting in CVD and the clinical signs that are observed indicate that there is inflammation, secondary to venous hypertension, and it leads to a number of inflammatory pathways that become activated. The endothelium and glycocalyx via specialized receptors are critical at sensing changes in shear stress, and expression of adhesion molecules allows the activation of leukocytes leading to endothelial attachment, diapedisis, and transmigration into the venous wall/valves resulting in venous wall injury and inflammatory cells in the interstitial tissues. There is a complex of cytokines, chemokines, growth factors, proteases and proteinases, produced by activated leukocytes, that are expressed and unbalanced resulting in an environment of persistent inflammation with the clinical changes that are commonly seen, consisting of varicose veins to more advanced presentations of skin changes and venous ulceration. The structural integrity of protein and the extracellular matrix is altered, enhancing the progressive events of CVD. Work focusing on metabolic changes, miRNA regulation, inflammatory modulation and the glycocalyx will further our knowledge in the pathophysiology of CVD, and provide answers critical to treatment and prevention.