The concept of zero and no-effect plays a major role in toxicology. Issues discussed in this chapter include the nature of the adverse responses produced at the level of the organism and population. Humans and animals evolved in an environment bathed in all sorts of chemicals. Some compounds were toxic and others beneficial and even essential, serving as nutrients and medicines. Even vitamins at low doses can be severely toxic at excessive doses. The historical transition of toxicology from the science of poisons to today’s focus on safety is the source of semantic confusion over interpreting terms ranging from poisonous, hazardous, having zero effect, and nothing happens. How serious must an adverse effect be to be considered toxicologically significant? The chapter follows the development of Paracelsus’ dictum “Dose makes the poison.” Different approaches to quantitating a toxicologic response are presented, paying particular attention to the difference between a no effect dose, and one that produces a mild effect that defines the metrics we use for safe limits of exposure, versus a maximum tolerable dose. Detection of a biological effect no different than seen in control animals, or the normal population, should not be of concern. Chemical exposure does not equate to toxicity.