This article draws on a subset of data from an empirical study supported by the National Science Foundation. The study explored how institutional review boards (IRBs) fulfill their obligations to oversee research that involves human subjects. The subset of data is used to discuss two themes that shed light on how IRBs approach issues that may have a bearing on protection of human subjects but that are not well covered by federal regulatory guidance. The authors conducted 40 semistructured, key informant interviews, over a 1-year period, with members of various types of IRBs, including independent, academic/university, hospital, medical school, and community/tribal IRBs. Among the 40 participants, there were 16 chairs (president, administrator) and 24 members, and 17 males and 23 females; most had served as IRB members for more than 5 years. The data from this study indicate that fulfillment of the IRBs’ oversight responsibilities may be undermined by a lack of regulatory guidance as to how much information should be disclosed to the IRB and to research participants about: (a) the purpose of a study including commercial purposes and (b) researcher/institutional compensation. The data suggest that without adequate regulatory guidance, IRBs may be meeting the letter but not the spirit of the federal regulations. The lack of regulatory guidance with respect to these two issues limits the extent to which IRBs can assess the adequacy of the consent process, the effectiveness of the IRB in performing oversight responsibilities, and optimal protection of human subjects.