The loss of estrogen at menopause is associated with an accelerated risk of cardiovascular diseases in women. Estrogen is known to impose protective effects on the cardiovascular system and until the menopausal transition, women have a lower prevalence of cardiovascular events compared to aged matched men.One functionally important impairment in the cardiovascular system with menopause is a reduced ability to regulate the vascular tone of peripheral arterioles, an impairment which, is associated with a reduced function of the nitric oxide and prostacyclin systems. Based on evidence from studies on men, it is generally accepted that exercise training leads to improved vascular function, in part by improved regulation of vascular tone of peripheral arterioles. Moreover, the nitric oxide and prostacyclin systems are trainable and are likely, in part, responsible for the beneficial effects of exercise training on vascular function. In men, even at older age, exercise training at a broad range of intensities and modalities improves vascular function whereas older women have been shown to be less responsive to exercise training, and thereby have poorer odds for improving their vascular health via physical activity. However, recent observations indicate that exercise intensity and time after menopause may be of importance for the efficacy of exercise training. The controversial observations that late post-menopausal women do not improve their vascular function by physical activity whereas vascular function is augmented to the same extent in pre-menopausal and early post-menopausal women gives rise to the exercise timing hypothesis which suggest that the timing of the initiation of exercise training after menopause determines how much vascular function is improved by a given training intervention. One potential mechanism behind the exercise timing hypothesis is the dynamics of the transcription factor estrogen-related receptor alpha (ERRα). From cell studies we know that skeletal muscle contraction activates the estrogen response element via a MAPK-PGC1α-ERRα pathway which ultimately can induces changes to vascular function by upregulation of endothelial nitric oxide synthase and improved antioxidant defense. In skeletal muscle biopsies from humans, ERRα expression is higher in recent post-menopausal compared to late pre-menopausal women after a training intervention suggesting that the ERRα pathway may become more important for the training response after the loss of estrogen. This talk will discuss the putative significance of the ERRα pathway in mediating the positive effects of physical activity on vascular function in post-menopausal women with a special focus on the nitric oxide and prostacyclin system. Data from topical highly invasive human studies on vascular function are included to highlight the current evidence for a connection between the estrogen-related receptor, estrogen deprivation and exercise training.