Many genomics specialists recognize that the massive genome rearrangements grouped under the term “chromoanagenesis” are a path to rapid evolutionary change by restructuring chromosomes, creating chimeric sequence combinations, and altering regulatory interactions leading to novel phenotypes. Less attention has been paid to the role of ubiquitous eukaryotic double-strand DNA break repair functions known as “alternative end-joining” (AltEJ) in generating additional DNA sequence innovation. A close look at some examples of chromoanagenesis rearrangements in the human germline and tumor cells illustrates how diverse these novel sequences can be. AltEJ creates sequence duplications and DNA insertions into junctions between chromosome breakpoints; these insertions range in size from a few base pairs up to many kilobases in length. The AltEJ insertions can come from nearby or distal sequences on one of the rearranged chromosomes, from another chromosome, or from de novo replication without template carried out by the versatile DNA polymerase theta, an enzyme known for its activity as an untemplated DNA terminal transferase. In a significant number of cases, the AltEJ insertions contain novel combinations of several segments copied from more than one region of the genome by a phenomenon known as “template switching.” By virtue of the combinatorial and creative actions of AltEJ in chromosome restructuring, massive genome change by chromoanagenesis contributes an apparently limitless range of DNA sequence innovation to eukaryotic evolutionary novelty.