A number of unique challenges apply to Emergency Department (ED) clinical research studies. While these challenges primarily relate to engaging the participant during the recruitment process, they also have consequences for adherence to the study protocol, including the post-ED treatment regimen and data collection during follow-up. First, we recognized that in contrast to other types of clinical trials that may identify potential study participants in a non-acute illness state through physician referral, advertising, patient databases, etc., patients usually present themselves to the ED in need of immediate care, especially pain relief. Thus, the willingness of a person in acute distress to be enrolled in a clinical trial may be reduced significantly. Second, there may be limited time between when both the pain is controlled and a diagnosis is confirmed and when the patient is discharged from the ED. Consequently, study staff may have limited time to explain the study to the patient, answer questions about the demands of the trial, and obtain written informed consent. This time pressure is exacerbated by the fact that the ED encounter is the only opportunity for eligibility screening and randomization. Because there may be insufficient time to establish a “personal” relationship with the potential study participant, the expectation of adherence to treatment and need for follow-up contact (only remote follow-up contact is performed) may not be as firmly established as in other recruitment settings. Third, study staff must collaborate with other ED staff and specialists to avoid treatment with the study drug or other contraindicated medications, to identify subjects with planned intervention or hospitalization, and to be aware of the need for specific testing as a prerequisite for inclusion. Finally, initial interest in participation may wane after discharge from the ED and resolution of symptoms thereby hindering follow-up contacts and the ability to obtain the primary outcome. In this presentation, we address these challenges and others and offer solutions that we have found successful.