Midlife decline in cognition, specifically in areas of executive functioning, is a frequent concern for which menopausal women seek clinical intervention. The dependence of executive processes on prefrontal cortex function suggests estrogen effects on this brain region may be key in identifying the sources of this decline. Recent evidence from rodent, nonhuman primate, and human subject studies indicates the importance of considering interactions of estrogen with neurotransmitter systems, stress, genotype, and individual life events when determining the cognitive effects of menopause and estrogen therapy. Hum Brain Mapp 35:847–865, 2014. © 2012 Wiley Periodicals, Inc.