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Ischemia and angina with non-obstructive coronary arteries (INOCA/ANOCA) have evolved into a defined clinical entity, with invasive coronary functional testing now guideline-recommended to establish the underlying endotypes. Yet diagnostic progress has outpaced pathophysiological understanding and therapeutic development. This article examines the principal unmet needs across INOCA/ANOCA: the observational nature of current registries; the unresolved molecular basis, natural history and overlap of the microvascular and vasospastic endotypes; persistent underdiagnosis and unstandardized invasive physiology; the absence of validated non-invasive tools and biomarkers; and the lack of endotype-targeted therapies proven to improve outcomes. Addressing these gaps is essential to advance mechanism-based personalized care.