Ciliates are unicellular protists that may have arisen more than a billion years ago. They have since diverged into thousands of species, many uncharacterized, the genetic divergence among ciliates being at least as deep as that between plants and animals. Despite their diversity, ciliates are united by two common features; the presence of short threads called cilia on their surface, whose rhythmic beating causes movement and is also useful for food capture, and the presence of two types of nuclei. The macronucleus contains DNA encoding functional copies of all the genes that regulate vegetative growth and cell proliferation. The micronucleus contains encrypted versions of the macronuclear DNA, is mostly functionally inert, and is only used for sexual exchange of DNA. In this chapter we study the decryption of the macronuclear DNA from a computational perspective. When two cells mate, they exchange micronuclear information. After they separate, the old micronuclei and macronuclei degenerate, while the newly formed micronuclei develop into new macronuclei over hours or days, depending on the species. Few ciliates have so far been studied at the level of molecular genetics: Tetrahymena and Paramecium representing the Oligohymenophorans and Oxytricha (recently renamed Sterkiella), and Stylonichia and Euplotes representing Spirotrichs. The DNA molecule in each of the approximately 120 chromosomes in the micronucleus contains on average approximately 107 basepairs (bp) in Oxytricha species and approximately 18 × 106 bp in Stylonichia lemn. The size of the DNA molecules in the macronucleus is, in contrast, very small. In various Oxytricha species and S. lemnae, macronuclear DNA molecules range in size from 400 to 15,000 bp with most molecules in the 1000–8000 bp range. Macronuclear DNA sequences are derived from the micronuclear sequences through a series of DNA rearrangements as follows. The segments that together constitute a macronuclear sequence (macronuclear destined sequences or MDSs) are present as sub-sequences in the micronuclear DNA. However, in the micronuclear DNA, MDSs are interspersed with long DNA sequences (internal eliminated sequences or IESs) that are excised in the micronucleus to macronucleus differentiation.