Background Untreated pain is common for patients at the end of life. Informal caregivers, often family or friends of patients, are responsible for working with hospice staff to provide pain management. Interdisciplinary team meetings conducted in hospices every 2 weeks provide an opportunity for hospice staff to communicate about pain management with informal caregivers of hospice patients. Purpose We present challenges, solutions, and keys strategies for carrying out a randomized trial in the hospice setting. Methods We are conducting the Assessing Caregivers for Team Intervention through Video Encounters (ACTIVE) study to determine whether regular videoconferencing between hospice patients informal caregivers and the hospice care team alters caregivers perceptions of pain management and patients pain. Participants must be primary caregivers for a hospice patient, at least 18 years of age, capable of providing informed consent, and have access to a computer with a high-speed Internet connection or a telephone. We randomized caregivers to participate in biweekly team meetings through video or phone conferencing (intervention) or to receive usual care from the hospice. All patients receive standard hospice care regardless of the group assignment of their informal caregiver. Results As of 1 July 2012, there have been 1038 new admissions to the participating hospices. Of 391 cases in which no contact was made, 233 patients had died or had life expectancy less than 14 days. Home visits were made to 271 interested and eligible caregivers; 249 caregivers of 233 patients were randomly assigned to the usual care or intervention arm. Enrollment is on pace to meet recruitment goals. Lessons Learned Thorough pilot testing of instruments and procedures helped us overcome barriers to conducting research in this vulnerable population. Keys to success included obtaining support from hospice medical directors, including hospice staff in study preparation, minimizing the burden on hospice staff, housing research staff in each participating hospice, using newsletters to enhance communication, developing and maintaining a detailed procedural manual, producing regular data quality reports, developing a secure site to facilitate coding videos for qualitative studies, and holding regular teleconferences with key staff. Limitations Late enrollment of many patients in hospice left little to no time for their caregivers to take part in the intervention. Assisting caregivers of patients with very short life expectancy may require different methods. Conclusions The challenges of conducting randomized trials with hospice patients and caregivers can be addressed with appropriate study design, well-tested research methods, and proactive monitoring of any issues or problems.