The immune system protects its host through a complex defence and attack system against pathogens. Allergy is an immunopathologic response, in which (re-)exposure to a substance that is often quite innocuous leads to undesirable outcomes, ranging from mildly bothersome symptoms to life-threatening anaphylaxis. This chapter starts with an overview of key players in the immune system, how they interact with one another in an allergic response and the application of these principles to the selection of investigations and pharmacotherapy in clinical allergy. The role of urbanization—elegantly conceptualized in the “Hygiene Hypothesis” and the more recent “Old Friends Hypothesis”—and genetics in the development of allergy are described. Finally, the atopic march, which refers to the natural history of allergic disease manifestation from infancy to childhood is discussed, and whether allergic disease can truly be prevented at all in susceptible individuals.