This review article draws on my decades of experience in the genetic engineering field. The article summarizes most of the currently used methods to modify the human genome, stressing how these methods can be used in gene and cell therapy strategies. In particular, the article explains the basis and evolution of editing methods that use a double-strand break, including meganucleases, zinc finger nucleases, TALENs, and the current CRISPR/Cas type systems. In addition, older methods that continue to be valuable are featured, including retrovirus, lentivirus, transposon, and site-specific recombinase approaches. Overall, the article provides a comprehensive overview of gene editing methods, how they evolved, and how they can be used in therapeutic strategies.