Chronic venous leg ulcers (CVLUs) affect approximately 600,000 people annually in the United States and accrue yearly treatment costs of US$2.5–5 billion. As the population ages, demands on health care resources for CVLU treatments are predicted to drastically increase because the incidence of CVLUs is highest in those ≥65 years of age. Furthermore, regardless of current standards of care, healing complications and high recurrence rates prevail. Thus, it is critical that factors leading to or exacerbating CVLUs be discerned and more effective, adjuvant, evidence-based treatment strategies be utilized. Previous studies have suggested that CVLUs' pathogenesis is related to the prolonged presence of high numbers of activated neutrophils secreting proteases in the wound bed that destroy growth factors, receptors, and the extracellular matrix that are essential for healing. These events are believed to contribute to a chronically inflamed wound that fails to heal. Therefore, the purpose of this project was to review studies from the past 15 years (1996–2011) that characterized neutrophil activity in the microenvironment of human CVLUs for new evidence that could explicate the proposed relationship between excessive, sustained neutrophil activity and CVLUs. We also appraised the strength of evidence for current and potential therapeutics that target excessive neutrophil activity.