A data monitoring committee (DMC) has special responsibilities for protecting the safety of clinical trial participants. Few guidance documents are available that address the operations and mechanics of establishing, serving on, or reporting to a DMC. This article provides a practical guide to sponsors, institutions, and individuals responsible for, or serving on, a DMC. Methods: A workgroup of professionals from academia and not-for-profit and commercial organizations that included investigators, statisticians, patient advocates, and ethicists met to define the essential elements of planning, coordinating, and populating a DMC. All members of the group have formed, served on, advised, or worked with DMCs. Results: The group outlined the objectives and mechanics of running a DMC, including operational and practical considerations, membership characteristics, roles, members’ liability, and indemnification. Further, it delineated the roles and responsibilities of each DMC member. Conclusions: The group recommended practices for each phase of the DMC process from inception through execution of a clinical trial, with appropriate considerations for confidentiality. The group’s practical guidance should assist in comprehensive oversight of appropriate clinical trials and should help DMC members execute their obligations with greater assurance. Keywords safety data, clinical trials, oversight of clinical trials, human subject safety, multi-site clinical trials, Data Monitoring Committees