This paper highlights the major challenges and considerations for addressing COVID-19 in informal settlements. It discusses what is known about vulnerabilities and how to support local protective action. There is heightened concern about informal urban settlements because of the combination of population density and inadequate access to water and sanitation, which makes standard advice about social distancing and washing hands implausible. There are further challenges to do with the lack of reliable data and the social, political and economic contexts in each setting that will influence vulnerability and possibilities for action. The potential health impacts of COVID-19 are immense in informal settlements, but if control measures are poorly executed these could also have severe negative impacts. Public health interventions must be balanced with social and economic interventions, especially in relation to the informal economy upon which many poor urban residents depend. Local residents, leaders and community-based groups must be engaged and resourced to develop locally appropriate control strategies, in partnership with local governments and authorities. Historically, informal settlements and their residents have been stigmatized, blamed, and subjected to rules and regulations that are unaffordable or unfeasible to adhere to. Responses to COVID-19 should not repeat these mistakes. Priorities for enabling effective control measures include: collaborating with local residents who have unsurpassed knowledge of relevant spatial and social infrastructures, strengthening coordination with local governments, and investing in improved data for monitoring the response in informal settlements.