Type 1 plasminogen deficiency (PLGD), an ultra-rare disorder caused by PLG pathogenic variants, results in decreased levels of immunoreactive and functional plasminogen. PLGD can cause fibrin-rich pseudomembranes on mucosa that impair tissue/organ function, impact quality of life, and are potentially life-threatening. Lesion regression/resolution is facilitated by intravenous administration of human plasma-derived Glu-plasminogen (IV PLG concentrate), the first and only FDA-approved specific treatment, licensed in 2021. The diagnosis of PLGD is frequently delayed due to its rarity (1.6 per million) and the variability of the initial medical specialty contact determined by the affected systems. Symptoms are often attributed to more common conditions, like conjunctivitis, recurrent otitis media, reactive airway disease, etc. This manuscript presents clinical vignettes highlighting strategies for PLGD diagnosis and treatment. Initial evaluation includes a detailed history, laboratory assays, and, at times, radiologic or other procedures. Genetic testing can confirm the diagnosis. Consistent, knowledgeable management is required to promptly identify and treat lesions, even in initially asymptomatic individuals. Personalized treatment may include continuous prophylaxis or intermittent treatment with IV PLG concentrate, dependent on disease severity and clinical course. Specialized facilities like Hemophilia Treatment Centers offering multidisciplinary care represent medical homes for this ultra-rare disorder.