The overall goal of this work is to address clinical unmet needs for patients with lipedema using advanced magnetic resonance imaging (MRI) methods of vascular and molecular dysfunction, in sequence with portable clinical measures of adiposity and edema. Specifically, lipedema is a disease marked by subcutaneous adipose tissue (SAT) accumulation in the lower extremities accompanied by somatic pain and edema, poor quality of life and significant psychological distress. Importantly, lipedema is commonly misdiagnosed as obesity, yet symptoms are refractory to interventions for obesity leading to delayed diagnosis typically 22 years after symptom onset. A recent call to action for lipedema highlights the need for additional lipedema research, as fundamental gaps persist in our knowledge regarding both disease mechanisms and potential treatments. Over the past five years and with support from the Lipedema Foundation, we have developed a whole-body imaging strategy for patients with lipedema to provide a more complete, quantitative perspective on condition features, as well as to refine appropriate imaging tools. We have demonstrated that lipedema is distinct from obesity using multi-modal fat-water MRI and limb bioimpedance. We optimized sodium and fat-fraction MRI to demonstrate significantly elevated tissue sodium and SAT volume in the lower extremities, but not upper extremities, of females with lipedema compared to matched controls. In preliminary data we demonstrate that skin sodium can be mobilized by a standard lymphatic therapy, complete decongestive therapy (CDT). Recent findings of elevated arterial perfusion and inflammatory profiles in lipedema raise significant questions about how blood and lymphatic circulation are involved in disease pathogenesis. Here we propose for the first time to apply molecular and vascular (blood and lymphatic) imaging together with common clinical tools to test the following hypotheses: Hypothesis (1): ultrasound can be used as a more accessible alternative to MRI for measuring subcutaneous fat deposition and distinguishing lipedema from obesity; Hypothesis (2): tissue sodium reduces following CDT in the lower extremities, but not in the untreated upper extremities, of patients with lipedema consistent with improvements in symptomatology; Hypothesis (3): lower-extremity blood flow velocity is elevated, while lymphatic flow velocity reduced, in patients with lipedema compared to matched controls. Impact: Successful completion of this study will (1) determine modalities appropriate for lipedema screening, (2) demonstrate effects of lymphatic stimulation on tissue sodium in lipedema, and (3) advance our understanding of the circulatory mechanisms involved in lipedema.