In general, the strict preservation of broad-scale structure is thought to be critical for maintaining the precisely tuned functionality of vertebrate genomes, although nearly all vertebrate species undergo a small number of programmed local rearrangements during development (e.g., remodeling of adaptive immune receptor loci). However, a limited number of metazoan species undergo much more extensive reorganizations as a normal feature of their development. Here, we show that the sea lamprey (Petromyzon marinus), a jawless vertebrate, undergoes a dramatic remodeling of its genome, resulting in the elimination of hundreds of millions of base pairs (and at least one transcribed locus) from many somatic cell lineages during embryonic development. These studies reveal the highly dynamic nature of the lamprey genome and provide the first example of broad-scale programmed rearrangement of a definitively vertebrate genome. Understanding the mechanisms by which this vertebrate species regulates such extensive remodeling of its genome will provide invaluable insight into factors that can promote stability and change in vertebrate genomes.