The Minnesota Department of Health began its unexplained critical illness and death due to possible infectious etiologies (UNEX) project in 1995. In 2006, it also began surveillance for all possible infectious disease-related and unexplained deaths investigated by medical examiners (MED-X). Surveillance for unexplained critical illness and death is focused on determining the etiology of an acute illness in a previously healthy person 50 years of age or younger whose illness is suggestive of an infectious disease. This article describes how the programs operate and how they have been able to identify the causes of a number of unexplained deaths in Minnesota. It also discusses the need for specimen collection, laboratory technologies used to identify infectious agents, and the importance of identifying etiologies of unexplained illnesses and deaths in order to prevent potential outbreaks in the greater population.