Introduction: Mastocytosis is a disorder characterized by an abnormal clonal accumulation and subsequent activation of mast cells within one or more organs. It is generally classified as either cutaneous, with or without systemic involvement, or systemic without cutaneous disease based on major and minor criterion. Indolent systemic mastocytosis (ISM) is a subclass of systemic mastocytosis with generally good prognosis. While the etiology of ISM is not completely understood, those who are affected typically have the KIT D816V mast cell receptor mutation. Given that ISM is mast cell mediated, patients predominantly present with a wide range of symptoms related to mast cell degranulation, including flushing, anaphylaxis, gastrointestinal disturbances, and bone pain that can cause disruption to quality of life. Case Presentation A 61-year-old Caucasian female presented for the evaluation of a pruritic rash on her trunk and extremities. The rash had persisted for 43 years and she described ongoing pruritus significantly impacting daily activities, particularly bathing with warm water, which made the itching unbearable. She also experienced episodes of brain fog predating menopause There was no history of angioedema, asthma, wheezing, abdominal symptoms, or bone pain. Her daughter was also affected by a similar condition. Dermatologic examination revealed innumerable reddish-brown macules and patches on the trunk and extremities, most concentrated on the lower legs. These lesions formed wheals when stroked firmly. A skin biopsy revealed abnormally increased mast cell concentration in the dermis. Laboratory studies showed elevated serum tryptase, low total protein, low globulin, and high albumin/globulin ratio. A bone marrow biopsy revealed multifocal dense mast cell infiltrates with absent iron stores. Genetic testing was negative for mutations in KIT D816V. The patient met criteria for ISM and her symptoms were managed by varying degrees with Omalizumab, Montelukast, Cetirizine, and topical Clobetasol. She continues to have flares to this date. Learning Points Cutaneous mastocytosis can reliably be diagnosed clinically using Darier’s sign, in which rubbing a lesion induces wheal formation due to mast cell degranulation. Additionally, while virtually all ISM cases are linked to the KIT D816V mutation, this patient’s genetic testing was negative for the mutation, suggesting an alternative disease mechanism. Recent advancements in therapy offer new treatment options, providing hope for patients who, like this one, have endured over 40 years of limited therapeutic success. ISM, though carrying a favorable prognosis, can significantly impact quality of life through persistent symptoms.