Chronic venous disease and venous leg ulceration are a common disease affecting millions of individuals. The fundamental problem is venous hypertension with resultant clinical manifestations of venous disease including varicose veins, skin changes, and venous leg ulceration. The pathophysiology leading to venous hypertension is complex and multifactorial, involving genetic predisposition, environmental factors, hormones, endothelial dysfunction, inflammatory cells and molecules and activation on the endothelium and vein wall, and disturbances in the balance of cytokines and matrix metalloproteinases. Understanding the pathophysiology of chronic venous disease and venous leg ulcers identifies cellular pathways, biomarkers, metabolic signatures, and cellular cross-talk for targeted therapy.