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Background: Chronic wounds on the leg (below the knee) are called leg ulcers. They have many causes, and thus patients with leg ulcers are treated by many different kinds of medical specialist. Appproximately 80% of sufferers have chronic venous insufficiency (CVI) and/or peripheral arterial occlusive disease (PAOD). Knowledge of the relevant differential diagnoses is important for appropriate treatment, particularly for patients with atypical findings or an intractable course., Methods: This article is based on publications retrieved by a selective search in PubMed, including current guidelines and expert recommendations., Results: The diagnostic evaluation of a leg ulcer can be structured according to the ABCDE rule. This involves individualized, targeted history-taking (anamnesis); bacteriological testing; clinical examination; ancillary testing, particularly for perfusion (defective vascular system); and extras, such as biopsies. Specifically, we present in this article the main aspects of the complex diagnostic evaluation of venous leg ulcers, arterial leg ulcers, vasculitis, vasculopathy, calciphylaxis, pyoderma gangrenosum, necrobiosis lipoidica, ecthyma, and squamous cell carcinoma. There remain many unsolved problems, including interactions between the various areas of clinical treatment and the relative paucity of relevant high-quality research., Conclusion: A timely differential-diagnostic evaluation for the many diseases that can cause leg ulcers, which require treatment from representatives of many different medical specialties and health professions, is a prerequisite for their effective individualized treatment.