New clinical evidence reveals that women develop fundamentally different coronary disease pathophysiology compared to men, with greater susceptibility to microvascular dysfunction and endothelial impairment despite experiencing paradoxically less severe myocardial ischemia at equivalent levels of coronary stenosis. Women also show distinct atheroma plaque characteristics and increased vulnerability to coronary dissection and vasospasm. This mechanistic divergence challenges the male-centric diagnostic framework that has dominated cardiovascular medicine for decades. The finding that women receive less guideline-recommended treatment and experience worse outcomes in acute coronary syndromes—particularly at younger ages—suggests current risk assessment tools systematically underestimate female cardiovascular risk. The research highlights how hormonal fluctuations, pregnancy complications, autoimmune conditions, and even transgender hormone treatments create unique risk profiles that standard protocols fail to capture. Most significantly, the data indicates that traditional diagnostic approaches may be fundamentally flawed when applied to female patients, potentially explaining decades of underdiagnosis and suboptimal outcomes. This represents a paradigm shift toward sex-specific cardiovascular medicine that could dramatically improve prevention and treatment strategies for half the population.