Data Monitoring Committees (DMCs) have an important role in safeguarding patient interests and enhancing trial integrity and credibility. To effectively fulfill these responsibilities, DMCs should be independent of study sponsors, study investigators and caregivers managing study participants. However, in real world settings where DMCs are in place, there are emerging practices that threaten to diminish the true independence of these committees. The purpose of this presentation is to enlighten those who have responsibilities in implementing the DMC process, or who are relying upon or participating in DMCs, about evolving issues that can meaningfully impact the DMC’s ability to remain sufficiently independent to be able to effectively address its mission. Informed by extensive experiences with DMCs, we identified specific issues that appear to have the likelihood of being most influential, both now and in the near future, with regard to the actual level of independence of DMCs. We provide insights into how these issues have emerged and to their importance, and then develop recommendations for approaches to effectively address these issues. Procedures should be in place enabling the DMC to be provided adequately comprehensive and current access to unblinded data on safety and efficacy, yet these procedures should ensure the confidentiality of interim data. The DMC meetings should be led by the DMC Chair, ideally with a meeting format that begins with a Closed Session. Creative new approaches are needed for the engagement of DMC members to increase the transparency that they are not employees of the sponsor of the trial. A DMC Charter is needed that outlines the roles and responsibilities of the DMC without the appearance of being a legal contract. While meaningful conflicts of interest (COI) are inappropriate, perceived COI cannot be completely avoided. Finally, it is essential to have proper indemnification in place that provides truly effective protection for DMC members. The independence of DMCs is of integral importance to their ability to effectively carry out their responsibilities. We need a wider recognition of this importance and of the influence of emerging practices on independence of DMCs, and a commitment to identify and implement creative approaches to enhance that independence.