The Defense Advanced Research Projects Agency (DARPA) is soliciting innovative proposals to identify and optimize novel molecules that exhibit inhibitory effects on Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-CRISPR associated proteins (CRISPR-Cas) gene editing processes. The Broad-Spectrum Antagonists for Editors (B-SAFE) program is explicitly seeking transformative approaches enabling the discovery or design of novel inhibitors of gene editing technologies with enhanced activity, utility, and breadth of coverage. Novel inhibitor activity will be assessed in vitro over the course of the program and a subset of top performing molecules will be selected for scale-up at quantities sufficient for testing and evaluation by Department of Defense (DoD) stakeholders. In concert, DARPA is interested in exploring methods to rapidly discover inhibitor molecules for novel gene editing technologies beyond CRISPR-Cas systems to keep pace with the rapidly advancing field and promote the safe, controlled use of these technologies. Research that generates incremental improvements to the existing state-of-the-art are specifically excluded.