All-cause mortality from cardiovascular disease is declining in the USA. However, there remains a significant difference in risk factors for disease and in mortality between men and women. For example, prevalence and outcomes for heart failure with preserved ejection fraction differ between men and women. The reasons for these differences are multifactorial, but reflect, in part, an incomplete understanding of sex differences in the etiology of cardiovascular diseases and a failure to account for sex differences in pre-clinical studies including those designed to develop new diagnostic and treatment modalities. This review focuses on the underlying physiology of these sex differences and provides evidence that inclusion of female animals in pre-clinical studies of heart failure and in development of imaging modalities to assess cardiac function might provide new information from which one could develop sex-specific diagnostic criteria and approaches to treatment.