Non-healing ulcers, especially those in diabetic patients, present an ongoing clinical challenge.This review identifies the main conditions that prevent the healing process and discusses the features of the wound environment, including the role of MMPs and serine proteases. EPA has been associated with non-healing wounds, and there are dressings (e.g., the collagen/ORC dressing) that are designed to help reduce EPA in the wound environment. There are no clinical signs related to EPA, and laboratory evaluations take time. We have used a protease status test that evaluates inflammatory protease activity in the wound environment in a short period of time and have suggested a guide that shows how this test may provide information to help a clinician decide which treatment is appropriate for a nonhealing ulcer.