Sex hormone signaling declines during aging, from early midlife through menopause, as a consequence of reduced circulating estrogens and decreased receptiveness to these hormones in target tissues. Estrogens preserve energy homeostasis and promote metabolic health via coordinated and simultaneous effects throughout the brain and body. Age-associated loss of estrogen production during menopause has been implicated in a higher risk for metabolic diseases and increased mortality. However, it remains unclear whether age-associated changes in homeostasis are dependent on reduced estrogen signaling during menopause. Although menopausal hormone therapies containing estrogens can alleviate symptoms, concerns about the risks involved have contributed to a broad decline in the use of these approaches. Non-hormonal therapies have emerged that target tissues or pathways with varying levels of selectivity, reducing risk. We summarize here the broad effects of estrogen loss on homeostasis during menopause, current and emerging therapies and opportunities for understanding homeostatic disruptions associated with menopause.