Retroviruses and related transposable elements, termed LTR retrotransposons, reside in the majority of eukaryotic genomes. In particular, endogenous retroviruses (ERVs) and LTR retrotransposons (LRs) constitute approximately 8% of the human DNA and 10% of the mouse genome. In some species, these selfish elements are still transpositionally active, i.e., able to self-reproduce in the host genomes, whereas in the other cases, LR/ERV copies accumulate deleterious mutations and cannot proliferate any longer. Regardless of their transpositional capacities, once inserted into the host cell DNA, the copies of LR/ERVs remain there forever. It is clear now that such newcomers, having a functional promoter, enhancer, polyadenylation signal, splice sites and even protein-coding open reading frames should not be considered simply junk DNA. The effect of their presence in the genome can be deleterious, neutral or advantageous to the host. Co-evolution of the original DNA and fixed LR/ERV-derived sequences created new regulatory networks for numerous eukaryotic genes. In this chapter, we review recent experimental findings evidencing the importance of LR/ERV DNA domestication by the host eukaryotic organisms for the progressive genome evolution as a whole, for normal gene functioning and for speciation processes. © 2009 by Nova Science Publishers, Inc. All rights reserved.