Clinical findings show sex differences in the manifestation of a number of cardiovascular diseases (CVD). However, the underlying molecular mechanisms are incompletely understood. Multiple animal models suggest sex differences in the manifestation of CVD, and provide strong experimental evidence that different major pathways are regulated in a sex-specific manner. In most animal studies females display a lower mortality, less severe hypertrophy, and better preserved cardiac function compared with male counterparts. The data support the hypothesis that female sex and/or the sex hormone estrogen (17β-estradiol; E2) may contribute to the sexual dimorphism in the heart and to a better outcome of cardiac diseases in females. To improve our understanding of the sex-based molecular and cellular mechanisms of CVD and to develop new therapeutic strategies, the use of appropriate animal models is essential. This review highlights recent findings from animal models relevant for studying the mechanisms of sexual dimorphisms in the healthy and diseased heart, focusing on physiological hypertrophy (exercise), pathological hypertrophy (volume and pressure overload induced hypertrophy), and heart failure (myocardial infarction). Furthermore, the potential effects of E2 in these models will be discussed.