Simple SummaryChronic progressive lymphedema (CPL) is a condition with a significant impact on the health and welfare of the current draft horse population. Clinical signs are severe and primarily involve the progressive swelling of the distal portions of the legs, which is accompanied by scaling, marked dermal fibrosis, and the development of skinfolds and nodules, which are often complicated by secondary infections. Current treatment and management options aim only at slowing down the disease’s progression. Despite the severity of this condition, many uncertainties regarding its etiology and pathogenesis still persist to date. Understanding and recognizing the clinical signs, as well as managing CPL, therefore, remain major challenges in current veterinary practice. This review discusses possible hypotheses for the pathogenesis of CPL in order to gain new insights and provide a clear perspective for future research. We also cover advances in CPL diagnosis and management, along with an illustrated overview of primary, secondary, and CPL-associated lesions. Furthermore, a renewed scoring system has been developed, which is based on new insights, to assess and grade clinical CPL severity in draft horses by using a uniform and simplified method of evaluation.AbstractChronic progressive lymphedema (CPL) in draft horses is characterized by increased dermal thickness and fibrosis, with the development of skinfolds and nodules, hyperkeratosis, and ulcerations on the distal limbs of affected horses. Secondary bacterial, fungal, or parasitic infections frequently complicate and aggravate the lesions, as well as the progression of this disease. CPL has a particularly high prevalence of up to 85.86% in the Belgian draft horse breed. Due to the disease’s progressive and incurable nature, affected horses are often euthanized prematurely. The treatment options are solely symptomatic, aimed at improving the horse’s quality of life. Despite the severity of this condition, many uncertainties about its etiology and pathogenesis still remain to date. The established scientific research on CPL is rather limited, although there is an urgent need for strategies to tackle this disease. This review summarizes the available knowledge, serving as a guideline for practitioners, and provides perspectives for future research programs.