Premenstrual dysphoric disorder (PMDD) is a severe mood disorder affecting women of reproductive age, characterized by a constellation of affective and physical symptoms that recur in the luteal phase of the menstrual cycle. This chapter addresses the current knowledge about the complex etiology of PMDD, highlighting the abnormal response to these hormonal changes and the potential roles of genetic predispositions and neurotransmitter dysregulation. Epidemiological findings on risk factors and biomarkers including genetic, inflammatory, and neuroimaging markers, offer promising avenues for risk stratification, improved diagnosis, and targeted therapy, emphasizing the importance of further research. The chapter emphasizes the profound impact PMDD has on women’s health and quality of life, advocating for advancements in this field to facilitate improved therapeutic strategies and outcomes for affected individuals.