Human and wild life populations are continually exposed to a wide variety of environmental estrogen-like chemicals. Most research to date on environmental endocrine disrupting estrogen-like chemicals has focussed on screening of estrogenic activity of environmental or industrial chemicals, their bioaccumulative properties and toxicokinetics, and developing the structure-activity relationship between environmental or industrial chemicals and estrogen-receptor. Whether estrogen-like chemicals also possess the ability to alter the stability of the genome is not clear. It is very important to understand the effects of estrogen-like chemicals at the genome level. This article evaluates the current status of knowledge of the potential of producing genomic instability in response to the exposure of estrogen-like chemicals, which might help in understanding the mechanisms of some of the adverse effects. We and others have shown several structural, numerical, and functional changes at the cellular levels in response to DES exposure. Some other phenolic estrogen-like chemicals, such as, bisphenol A, phenylphenol and nonylphenol, also follow some of the pattern of effects similar to DES. These compounds also alter cell cycle kinetics, induce DNA damages, and produce telomeric associations and chromosomal aberrations. Whether weak or strong, the estrogenic response of a chemical, if not overcome, will add extra estrogenic burden to the system, and particularly those endocrine disrupting environmental and industrial estrogen-like chemicals capable of producing genomic instability will induce additional burden of genomic instability. Though, estrogenically some of these compounds may be weak, however, they may have different activities in generation of genomic instability. For example, nonylphenol is weak in estrogen-like action compared to DES, however, it is equal or more potent in producing telomeric associations in MCF-7 cells compared to DES. Additive or synergistic extra-burden of estrogenicity and genomic instability could produce detrimental effects compare to estrogenic action alone. Screening of endocrine disrupting environmental estrogen-like chemicals for their ability to produce genomic instability and analysis of molecular basis of some of the adverse human health outcomes as a result of exposure of these types of chemicals should lead to a better understanding of how these environmental estrogen-like chemicals may influence the development of some adverse effects in humans and wildlife.