Background: A diagnosis of hereditary angioedema (HAE) with normal C1 esterase inhibitor (HAE-nl-C1-INH) can be challenging and pharmacologic management is not well defined. Objective: The objective was to discuss practical considerations in the clinical management of HAE-nl-C1-INH by using illustrative clinical vignettes to highlight and/or address select challenges. Methods: This was a narrative review. Results: Symptoms of HAE-nl-C1-INH overlap with HAE types I and II; the heterogeneity of presentation and symptom burden are diagnostic challenges. A patient history, with particular attention to whether urticaria or other symptoms of mast cell mediator release are present, is important because such symptoms would strongly suggest a mast cell-mediated pathway. A family history of angioedema is informative but a lack thereof does not rule out diagnosis. Expected laboratory findings would be normal for C4, C1-INH level and function, and Complement 1q; a genetic mutational analysis may be helpful, but current assays do not include all known mutations; most cases are categorized as unknown. To align with guideline-directed treatment approaches, the following stepwise approach is suggested for suspected HAE-nl-C1-INH: (1) thoroughly investigate the possibility of response to histaminergic and/or mast cell-targeting treatments; (2) if patients with normal C4, C1-INH level and/or function fail adequate trials with histamine/mast cell-directed therapy or have a mutation that suggests bradykinin pathway involvement, follow HAE type I and II treatment guidelines. Response to medications approved for HAE types I/II provides compelling support for a high clinical suspicion of HAE-nl-C1-INH. De-labeling an HAE-nl-C1-INH diagnosis may be appropriate if the initial diagnosis was made without adequate evaluation or if new information and/or testing indicates that the patient does not actually have HAE. Conclusion: Key unmet needs in HAE-nl-C1-INH include lack of confirmatory biomarker(s) for diagnosis and lack of prospective controlled clinical studies of pharmacologic products in this patient population.