Practice-based research raises unique challenges with respect to human subjects protections and institutional review board (IRB) review. In this paper, three challenges posed by practice-based research are analyzed: (1) IRB review for clinician investigators who are not affiliated with an institution that has an IRB; (2) multiple IRB review; and (3) required human subjects protection training of key personnel. Investigators should be proactive in addressing required IRB review in practice-based research. In particular, they need to ensure that appropriate IRB review is obtained for all performance sites and plan for review for unaffiliated investigators. Practice-based research investigators and professional societies should educate IRB members and policy makers and publish articles regarding how IRBs might best address human subjects concerns in practice-based research. Furthermore, practice-based research investigators and professional societies should work with IRBs and the Office for Human Research Protections to facilitate centralized or cooperative review of practice-based research. Finally, practice-based research investigators need to ensure that their clinician investigators receive appropriate training in human subjects protection. Practice-based research investigators and professional societies can facilitate this process by helping to define and implement the appropriate training for busy practice-based research clinicians and office staff.