Background: Although variations among institutional review boards (IRBs) have been documented for 30 years, they continue, raising crucial questions as to why they persist as well as how IRBs view and respond to these variations. Methods: In-depth, 2-hour interviews were conducted with 46 IRB chairs, administrators, and members. The leadership of 60 U.S. IRBs were contacted (every fourth one in the list of the top 240 institutions by NIH funding). IRB leaders from 34 of these institutions were interviewed (response rate = 55%). Results: The interviewees suggest that differences often persist because IRBs think these are legitimate, and regulations permit variations due to differing “community values.” Yet, these variations frequently appear to stem more from differences in institutional and subjective personality factors, and from “more eyes” examining protocols, trying to foresee all potential future logistical problems, than from the values of the communities from which research participants are drawn. However, IRBs generally appear to defend these variations as reflecting underlying differences in community norms.Conclusions: These data pose critical questions for policy and practice. Attitudinal changes and education among IRBs, principal investigators (PIs), policymakers, and others and research concerning these issues are needed.