The current review highlights gender-specific issues in ischemic heart disease (IHD) presentation, evaluation, and outcomes with a special focus on the results derived from the National Institutes of Health-National Heart, Lung, and Blood Institute-sponsored Women's Ischemia Syndrome Evaluation (WISE) study. New evidence on gender-based differences in vascular wall, atherosclerotic plaque deposition, pathophysiology, and innovative cardiovascular imaging techniques are reviewed. Critical areas of further inquiry needed to advance new gender-specific IHD understanding are detailed.