Persistence of DNA vectors in target cells is advantageous in most applications of gene therapy. Particularly when target cells are undergoing proliferation, vector longevity will depend on either the integration of the vector into the chromosomes or the ability of the vector to replicate and be retained extrachromosomally. Vectors that efficiently integrate in a nonrandom fashion are currently unavailable, and those that can replicate extrachromosomally provide a major alternative strategy. Several classes of such vectors are under development, carrying mechanisms for prolonging DNA retention in mammalian nuclei that extend vector lifetime in non-proliferating cells as well. The vectors utilize either chromosomal or viral elements to mediate replication and retention, and have a large size capacity for insertion of genes of interest. I discuss the state of the art for these vectors, including the assets and limitations of their future use in gene therapy.