A large number of diverse nonsteroidal chemicals, referred to as xenoestrogens, bind to the estrogen receptor (ER) and evoke biological responses. The activity of most xenoestrogens is weak (from about 1/1000 th to 1/1000000 th that of estradiol). These substances interact with the binding pocket of the ER because they have chemical similarities to estradiol (usually a phenolic A-ring). Reduced activity of xenoestrogens probably results from lack of fit of the remainder of the molecule within the binding pocket. ER binding per se has only limited influence on endocrine disruption. The nature (estrogenic or antiestrogenic) or magnitude of the response is a function of the substance itself, complexities within the various stages of the ER signaling pathway, as well as other factors (such as, plasma binding of xenoestrogens, cross-talk between ER and other signaling pathways, androgen antagonism, and alternate modes of estrogen action). Whereas there is general agreement that high doses of nonsteroidal chemicals can evoke endocrine disruptive effects, there is no consensus that such substances produce low-dose effects or that humans are at risk of endocrine disruption due to exposure to environmentally relevant levels of such chemicals. Furthermore, screening programs to identify hormonally active chemicals (such as the Endocrine Disruptor Screening Program) may be premature in view of the complexity of the mechanisms involved.