In the present review we discuss recent findings showing that, in addition to the canonical estrogen receptor-alpha (ERalpha), the level of various ERalpha splice variants is changed in the human brain in aging and Alzheimer's disease (AD) at both the mRNA and protein level and that they should be considered for the understanding of estrogen effects on the brain and estrogen therapy pitfalls. Indeed, the expression pattern of certain splice forms is brain area-specific. Thus, the major isoform found in the mamillary body (MB) appeared to be del.7 (deletion of exon 7), while in the hippocampus del.4 (exon 4 omitted) was expressed at the highest level. Furthermore, while transcripts missing exons 7 and 2 declined with aging in the MB of patients >60 years old, no age-related alterations were determined for a number of splice variants in the hippocampus. A novel MB1 isoform with a 168-bp deletion within the transactivation function 1 of ERalpha turned out to accumulate in the histaminergic tuberomamillary nucleus of postmenopausal women. Finally, the level of alternatively spliced ERalpha may also change in AD in a brain area-specific manner and so affect the sensitivity to estrogen therapy.