Genomewide DNA rearrangements occur in many eukaryotes during development, but their functions and mechanisms are poorly understood. Previous studies have implicated a sequence-recognition mechanism based on RNA-mediated interactions between nuclei in ciliated protozoa. In this study, we found that the process recognized and deleted a foreign gene integrated in a Tetrahymena chromosome, suggesting an unusual mechanism of genome surveillance. We further found that injection of double-stranded RNA into the cell at specific developmental stages triggers efficient deletion of the targeted genomic regions. Together the results indicate an RNA-based mechanism that directs genomewide DNA rearrangements and serves to disable invading genetic agents.