Wound healing is a complicated and integrated process. Although there is some tolerance in terms of redundancy and interrelated control mechanisms, pushing beyond such limits may contribute to delayed wound healing, and in extreme cases lead to chronic wounds/ulcers and thus potentially to lower extremity amputation. Diabetes is associated with such disruption in wound healing. Research in humans and in animal models has identified a large number of changes associated with diabetes at the molecular level in delayed wound healing and to a lesser extent in chronic diabetic ulcers. Better overall understanding of these changes and how they are interrelated would allow for specifically targeted treatment, thus ensuring improved quality of life for patients and providing savings to the high costs that are associated with all aspects of chronic diabetic ulcers. This review examines the work done at the molecular level on chronic diabetic ulcers, as well as considering changes seen in diabetes in general, both in humans and animal models, that may in turn contribute to ulcer formation.