BACKGROUND: Chronic edema affects millions of people in the United States and worldwide. Edema can result from a variety of diseases, trauma, medications, and other contributing factors; however, all edema is related to lymphatic fluid dysregulation. Additionally, lymphatic impairment and integumentary dysfunction are interrelated, leading to complex clinical presentations that require an integrated medical model of care to maximize outcomes. PURPOSE: This narrative review article will highlight the current evidence that details lymphatic physiology, fluid regulation by the endothelial glycocalyx layer, and the interconnectedness of the vascular and integumentary systems leading to a paradigm shift in our understanding of edema, lymphedema, and chronic wounds. Traditional pedagogy remains siloed with respect to the body systems, whereas current evidence indicates a certain interdependence, particularly between and among the venous, lymphatic, and integumentary systems. METHODS: Comprehensive narrative review of the current and past literature (2010–2021 through PubMed, Google Scholar, MEDLINE Complete, UpToDate) focusing on lymphatic physiology, fluid regulation, the endothelial glycocalyx layer, lymphedema, and venous insufficiency. Review focuses on new evidence supporting the interconnectedness of the systems to support a unified medical management approach. RESULTS: All edema is related to lymphatic dysfunction, whether transient or permanent, thereby creating a lymphedema continuum. Further, lymphatic impairment creates cutaneous regions of skin barrier failure, rendering the skin more susceptible to breakdown and chronic wounds. CONCLUSION: A synthesis of the current evidence suggests an interconnected relationship of the lymphatic, venous, and integumentary systems, highlighting the need for a more integrated medical model of care to provide efficient and comprehensive care and improve patient outcomes.