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It is increasingly clear that not all estrogenic treatment regimens are alike with respect to effects on the brain, and that alternative regimens need to be evaluated and compared. In this chapter, Li and Al-Azzawi discuss the advantages of intranasal pulsatile estradiol administration relative to oral or transdermal therapies. Pharmacokinetic analyses demonstrate the feasibility of using intranasal pulsatile estradiol treatments to produce estradiol exposures comparable to those achieved via a transdermal route. As with transdermal therapies, intranasal application avoids the negative effects on liver enzymes associated with oral treatment. Major differences in the effects of pulsatile vs. sustained estradiol administration on gene expression have been detected. In addition, there are noted potential advantages of pulsatile vs. sustained treatment such as up-regulation of estrogen receptors, initialization of estrogen receptor co-factors, repeated activation of non-genomic pathways, and lower levels of potentially active (and carcinogenic) metabolites.