The higher cardiovascular risk in men and post-menopausal women implies a protective action of estrogen. A large number of experimental studies have provided strong support to this concept. However, the recent clinical trials with negative outcomes regarding hormone replacement therapy call for “post hoc” reassessment of existing information, models, and research strategies as well as a summary of recent findings. Sex steroid hormones, in particular estrogen, regulate numerous processes that are related to the development and progression of cardiovascular disease through a variety of signaling pathways. Use of genetically modified models has resulted in interesting information on diverse actions mediated by steroid receptors. By focusing on experimental findings, we have reviewed hormonal, cellular, and signaling mechanisms responsible for sex dimorphism and actions of hormone replacement therapy and addressed current limitations and future directions of experimental research.