Introduction Systemic Mastocytosis (SM) is a disorder characterized by the excessive accumulation and activation of mast cells (MC) in various organs. Many biomarkers have proven to be helpful in disease screening and diagnosis. Namely, serum tryptase, urinary N-methylhistamine, leukotriene E4 (LTE4) and prostaglandin F2 alpha (PGF2α). Our purpose is to describe a case of Indolent SM (ISM) with normal MC biomarkers. Case Description This is a 30 y.o. female who presented with a 10-year history of headaches, clouding of consciousness, syncope, intermittent abdominal pain, nausea, diarrhea, bone pain, skin flushing and suspected episodes of anaphylaxis. Serum tryptase, 24-hour urinary N-methylhistamine, PGF2α and LTE4 were all within normal limits. Blood molecular studies confirmed KITD816V point mutation. Skin biopsy showed mastocytosis with features of telangiectasia macularis eruptiva perstans. Bone scan was consistent with bony remodeling for MC disease. Ultimately, bone marrow (BM) biopsy showed low-level (25%) exhibiting an atypical spindle shape morphology, immunohistochemistry detected aberrant CD5 and CD2 co-expression confirming SM. Discussion Cutaneous and ISM have a good prognosis with similar survival rates compared to the general population. However, close monitoring may be warranted in SM patients, since a low-rate progression has been reported. The relationship between biomarkers and symptomatology and MC burden is not completely understood nor are the sensitivities of the tests. In the right clinical setting, clinicians should proceed with bone marrow biopsy, immunohistochemistry and molecular studies for a prompt and accurate diagnosis regardless of the status of the above mentioned serum and urine MC biomarkers. Systemic Mastocytosis (SM) is a disorder characterized by the excessive accumulation and activation of mast cells (MC) in various organs. Many biomarkers have proven to be helpful in disease screening and diagnosis. Namely, serum tryptase, urinary N-methylhistamine, leukotriene E4 (LTE4) and prostaglandin F2 alpha (PGF2α). Our purpose is to describe a case of Indolent SM (ISM) with normal MC biomarkers. This is a 30 y.o. female who presented with a 10-year history of headaches, clouding of consciousness, syncope, intermittent abdominal pain, nausea, diarrhea, bone pain, skin flushing and suspected episodes of anaphylaxis. Serum tryptase, 24-hour urinary N-methylhistamine, PGF2α and LTE4 were all within normal limits. Blood molecular studies confirmed KITD816V point mutation. Skin biopsy showed mastocytosis with features of telangiectasia macularis eruptiva perstans. Bone scan was consistent with bony remodeling for MC disease. Ultimately, bone marrow (BM) biopsy showed low-level (25%) exhibiting an atypical spindle shape morphology, immunohistochemistry detected aberrant CD5 and CD2 co-expression confirming SM. Cutaneous and ISM have a good prognosis with similar survival rates compared to the general population. However, close monitoring may be warranted in SM patients, since a low-rate progression has been reported. The relationship between biomarkers and symptomatology and MC burden is not completely understood nor are the sensitivities of the tests. In the right clinical setting, clinicians should proceed with bone marrow biopsy, immunohistochemistry and molecular studies for a prompt and accurate diagnosis regardless of the status of the above mentioned serum and urine MC biomarkers.