Heterogeneous presentations of disease pose particular diagnostic and management challenges to the clinician. Progestogen hypersensitivity (PH) classically consists of hypersensitivity symptoms to endogenous progesterone during the luteal phase of the menstrual cycle. However, with the rise of assisted fertility and the exponential growth in the use of exogenous progestins for contraception, PH’s prevalence and symptom heterogeneity have increased. In this article, we focus on the clinical approach to PH diagnosis with an emphasis on key elements of the history, physical, and testing modalities. We also review the current evidence for successful management and treatment across a broad range of patients.