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A progressive disease, lipedema is characterized by bilaterally symmetrical and disproportional accumulation of subcutaneous adipose tissue (SAT) in the extremities, leading to severe pain, inflammation, and mobility issues. Lipedema predominantly affects women in all stages of life and treatment options are currently limited as patients' conditions can only be improved to a limited extent by diet or exercise. The pathogenesis of lipedema remains poorly understood and a reliable diagnostic marker is currently missing. Disease progression is marked by stage-dependent morphological adipose tissue changes, such as adipocyte hypertrophy and stage-dependent fibrosis, accompanied by an elevated proportion of anti-inflammatory macrophages. The molecular mechanisms regulating these compositional and structural changes in adipose tissue, and to what extent this altered response is cause or consequence of the disease, remain unclear. Therefore, the analysis of disease-related changes, with a focus on the cellular dynamics and tissue composition changes may help to distinguish lipedema more reliably from adiposity-related comorbidities.