Programmed elimination of DNA during development yields somatic cell nuclei with dramatically different DNA sequence and content relative to germline nuclei, profoundly influencing genome architecture and stability. Whole-genome sequencing has significantly expanded the list of taxa known to exhibit this trait and has revealed the identity of excised genes and transposable elements (TEs) in certain taxa. Here, we compare the diverse mechanisms employed by ciliates, nematodes, copepods, and lamprey to downsize their genomes during development and propose tests of hypotheses about the evolution and/or maintenance of this trait. We explore possible functional roles that programmed DNA elimination (PDE) could play in genomic defense (especially against TEs), regulation of development, sex determination, co-option, and modulating nucleotypic effects, which together argue for a place in the mainstream investigation of genome evolution.