Aspirin is a generally well-tolerated drug that is now widely used in aged patients for its antithrombotic action. Aspirin works through several pathways to reduce inflammation, fever and to alter platelet activity. The scientific literature suggests that inhibition of the cyclooxygenase enzymes by aspirin or other nonsteroidal anti-inflammatory drugs may be deleterious to normal wound repair processes and result in healing inhibition. However, novel effects of aspirin on other pathways that regulate inflammation and repair have been reported more recently. These pathways, including inhibition of inflammatory second messengers and transcription factor pathways and production of anti-inflammatory, pro-resolution factors (lipoxins), provide a possible explanation for beneficial effects of aspirin in chronic wound healing. There have been limited studies to date that provide good evidence to support aspirin use in chronic venous leg ulcers but this may change as we see results from randomized trials that are currently being undertaken. In this article, we look at possible effects that aspirin administration may have on venous leg ulcer healing and the expanding knowledge of potential beneficial effects of aspirin that operate via novel pathways. Though the literature suggests that aspirin treatment and cyclooxygenase inhibition may have deleterious effects in normal healing, it is possible that in chronic wounds that may be trapped in an inflammatory state that aspirin treatment may result in beneficial outcomes.