Medical devices fabricated from the tissues of animals have been used for decades to repair failing human tissues and organs. Only recently, however, the notion that these tissues can be processed in ways that retain the natural structure and composition of the extracellular matrix (ECM) and then implanted without inciting adverse immune system reactions has become reality. Because natural ECM contains a complex composition of biologically active molecules able to assist in the restoration of a functional ECM when the patient's ECM is characterized by abnormal levels of pro-inflammatory factors and matrix-degrading enzymes, naturally occurring ECM can be used as a strategy to induce healing in both chronic skin ulcers and in chronic, complex fistulas. In this article, we compare the functional ECM deficiencies that make fistulas similar to chronic skin wounds, describe how natural ECM processed into a biologic graft material can be used to treat these conditions, and review the clinical evidence that demonstrates the effectiveness of these therapies in promoting healing in both body systems.