Disease outbreaks have been some of the most impactful events in the history of cities. The specter of plague and other epidemics provides stories of dreaded rapid social disruption and in some cases social collapse. The objective of this application chapter is to investigate through a set of case studies how disease outbreaks and epidemics can rapidly shift from a stress to a crisis and in turn drive significant policy transitions and transformations. The chapter introduces how disease crises disrupt daily life in cities and what have been some basic approaches in response. The chapter examines four cases of disease outbreaks that resulted in crises and significant transitions. The examples include two bubonic plague outbreaks (Marseille, France, in the 1720s; Hong Kong, China, in the late 1890s), one flu event (Spanish flu in St. Louis, US, in 1918), and COVID-19 spread (in Seoul, Korea, in 2020). The cases illustrate how the rapid onset of disease simultaneously severely disrupted everyday life and brought on a sudden health crisis that was built upon existing social and economic tensions.