Emerging and re-emerging infectious diseases pose growing global public health threats. However, research on and development of medical countermeasures (MCMs) for such pathogens is limited by the sporadic and unpredictable nature of outbreaks, lack of financial incentive for pharmaceutical companies to develop interventions for many of the diseases, lack of clinical research capacity in areas where these diseases are endemic, and the ethical dilemmas related to conducting scientific research in humanitarian emergencies. Hence, clinicians providing care for patients with emerging diseases are often faced with making clinical decisions about the safety and effectiveness of experimental MCMs, based on limited or no human safety, preclinical, or even earlier product research or historical data, for compassionate use. Such decisions can have immense impact on current and subsequent patients, the public health response, and success of future clinical trials. We highlight these dilemmas and underscore the need to proactively set up procedures that allow early and ethical deployment of MCMs as part of clinical trials. When clinical trials remain difficult to deploy, we present several suggestions of how compassionate use of off-label and unlicensed MCMs can be made more informed and ethical. We highlight several collaborations seeking to address these gaps in data and procedures to inform future clinical and public health decision making.