When the discovery of ERβ was reported in 1996 [1], many endocrinologists thought that, since this receptor had gone unnoticed for so long, it must be some sort of vestigial receptor with no function in the endocrinology of estrogen. This idea was quickly dispelled when ERβ-/- mice were created and found to have severely compromised ovarian function and prostatic hyperplasia [2]. Later, two other ERβ-/- mouse lines were created independently in two other laboratories and all three mouse lines were shown to exhibit severe ovarian dysfunction [3–5]. Moreover since the ovarian phenotype in ERβ-/- mice is distinctly different from that in ERα-/- mice [3, 6], it became clear that ERα and ERβ have distinct roles in the body. There is, at present, some argument between different labs concerning other aspects of the ERβ-/- phenotype. If biology was as straight forward as physics, where for each action there is an equal and opposite reaction, understanding knock out phenotypes would be easy. Unfortunately, in endocrinology, it is impossible to make a single alteration without eliciting a cascade of responses.