Outbreaks in which most or all persons were exposed to the same suspected source of infection, so-called universal exposure, are common. They represent a challenge for public health specialists because conducting analytical studies in such investigations is complicated by the absence of a nonexposed group. We describe different strategies that can support investigations of outbreaks with universal exposure. The value of descriptive epidemiology, extensive environmental investigation, and the hypothesis-generation phase cannot be overemphasized. An exposure that seems universal may in fact not be universal when additional aspects of the exposure are taken into account. Each exposure has unique characteristics that may not be captured when investigators rely on the tools readily at hand, such as standard questionnaires. We therefore encourage field epidemiologists to be creative and consider the use of alternative data sources or original techniques in their investigations of outbreaks with universal exposure.