Endocrine disrupters (ED) represent a good challenge for experimental toxicology. In order to deal with several critical points relevant to risk assessment: (a) ED may induce long-term effects upon exposure in susceptible developmental phases, including postnatal life up to puberty; thus, efforts are required to refine testing strategies, for example, by supporting the two-generation rodent study with a comprehensive in vitro/in vivo screening battery; (b) due to the regulatory role of endocrine homeostasis, mechanisms of endocrine disruption may impact on immune, neurobehavioral, and reproductive development, as well as on susceptibility to cancer; (c) the potential multiple exposure to ED with common targets through diet and/or living environment calls for the development of models to understand mechanisms of interactions and effects of mixtures; and (d) last but not least, ED may interact with a number of factors related to differential vulnerability of individuals or population subgroups, including the intake of nutrients or bioactive food components. Besides reducing the chance for noxious chemicals to enter our life, toxicological research on mechanisms may also lead to the definition of possible biomarkers of exposure, effect, and susceptibility that may be further exploited in human health surveillance.