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Lipedema is a chronic, multifactorial disorder characterized by connective tissue dysregulation, in which vascular dysfunction plays a significant role. Lipedema manifests as symmetrical, painful accumulation of adipose tissue, predominantly in the lower body and arms, with progressive pain, tissue heaviness, and soft-tissue changes across disease stages. Emerging evidence from the micro-to macro-scale implicates endothelial dysfunction, aberrant angiogenesis, and vessel fragility in the pathological accumulation of interstitial fluid leading to tissue edema. Vascular changes are compounded with extracellular matrix remodeling in the form of adipose tissue expansion and fibrosis. Immune cell infiltration and chronic inflammation further contribute to tissue stiffening and adipose hypertrophy, highlighting the role of immune-mediated mechanisms in disease progression. The interplay between vascular, lymphatic, connective tissue, and immune dysfunction emerges as a central determinant of lipedema pathophysiology. Understanding these interconnected mechanisms is critical for elucidating the fundamental biology of lipedema, identifying novel biomarkers, and guiding the development of translational interventions and optimized clinical management strategies.