The discovery of a second estrogen receptor, ERbeta, and the finding that 5alpha-androstane-3beta,17beta-diol (3betaAdiol) strongly binds to ERbeta, have opened up a new aspect of estrogen signaling. Some of the major shifts in our understanding come from finding ERbeta in tissues which do not express ERalpha but are estrogen-responsive; these were called sites of 'indirect estrogen action'. Two key sites that fall into this category are the brain and the prostate. Studies of ERbeta in the past 10 years have led us to hypothesize that estrogen signaling depends on the balance between ERalpha and ERbeta, and that inadequate predominance of one or the other isoform could lead to disease.