Gender difference is well recognized as a key risk factor for cardiovascular disease (CVD). Estrogen, the primary female sex hormone, improves cardiovascular functions through receptor (ERα, ERβ, or G protein-coupled estrogen receptor)-initiated genomic or non-genomic mechanisms. Gaseous signaling molecules, including nitric oxide (NO), hydrogen sulfide (H2S), and carbon monoxide (CO), are important regulators of cardiovascular function. Recent studies have demonstrated that estrogen regulates the production of these signaling molecules in cardiovascular cells to exert its cardiovascular protective effects. We discuss current understanding of gaseous signaling molecules in cardiovascular disease (CVD), the underlying mechanisms through which estrogen exerts cardiovascular protective effects by regulating these molecules, and how these findings can be translated to improve the health of postmenopausal women.