This chapter charts and critically analyses the ethical challenge of assessing how much (and what kind of) evidence is required for the justification of interventions in response antibiotic resistance (ABR), as well as other major public health threats. Our ambition here is to chart and briefly discuss main issues, and point to ways in which these need to be further advanced in future research. This will result in a tentative map of complications, underlying problems and possible challenges. This map illustrates that the ethical challenges in this area are much more complex and profound than is usually acknowledged, leaving no tentatively plausible intervention package free of downsides. This creates potentially overwhelming theoretical conundrums when trying to justify what to do. We therefore end by pointing out two general features of the complexity we find to be of particular importance, and a tentative suggestion for how to create a theoretical basis for further analysis.