Ciliates are champions in programmed genome rearrangements. They carry out extensive restructuring during differentiation to drastically alter the complexity, relative copy number, and arrangement of sequences in the somatic genome. This chapter focuses on the model ciliate Tetrahymena, perhaps the simplest and best-understood ciliate studied. It summarizes past studies on various genome rearrangement processes and describes in detail the remarkable progress made in the past decade on the understanding of DNA deletion and other processes. The process occurs at thousands of specific sites to remove defined DNA segments that comprise roughly one-third of the genome including all transposons. Interestingly, this DNA rearranging process is a special form of RNA interference. It involves the production of double-stranded RNA and small RNA that guides the formation of heterochromatin. A domesticated piggyBac transposase is believed to cut off the marked chromatin, and the retained sequences are joined together through nonhomologous end-joining processes. Many of the proteins and DNA players involved have been analyzed and are described. This link provides possible explanations for the evolution, mechanism, and functional roles of the process. The article also discusses the interactions between parental and progeny somatic nuclei that affect the selection of sequences for deletion, and how the specific deletion boundaries are determined after heterochromatin marking.