Two of the most studied brain areas related with learning and memory are prefrontal cortex and hippocampus. However, serious inconsistencies arise when these regions are analyzed in relation to the role of estrogens on cognitive deterioration. Some of these contradictions are reviewed in the context of the recently proposed critical period hypothesis, which takes into account the frame-time after cessation of ovarian function. Other factors related with cognition and influenced by estrogens include their role on; a) cholinergic central transmission, b) spinogenesis and synaptogenesis at hippocampus, and c) classical genomic and rapid non genomic effects. Understanding the cellular and molecular basis of these phenomena is vital for designing novel therapeutic actions applicable to human health and disease.