Patients who present with typical features of mast cell activation with laboratory confirmation and without evidence of a clonal mast cell disorder or other medical condition should be initiated on medical treatment to block mast cells and their mediators. If a major response is achieved, a diagnosis of nonclonal mast cell activation syndrome (NC-MCAS) is likely and treatment should be optimized, including management of any associated conditions. In this review, the latest evidence with regard to the diagnosis and treatment of NC-MCAS is presented.