Endogenous genome targeting and editing in an efficient and specific manner are technological challenges, particularly in development and translational settings, with significant foreseeable impacts on healthcare. To address these challenges, triplex-forming molecules, composed of oligonucleotides or peptide nucleic acids, target and elevate the cell’s own DNA repair and recombination machinery by forming triplex structures with duplex genomic DNA. Once elevated, recombinagenic molecules co-opt this DNA repair and recombination machinery to introduce edits into the genome. Cells drugged with these designed molecules for triplex-formation and for recombination, and primed with chemical cell modulators, safely and effectively target and edit the genome for physiological gene correction, induction, and regulation. This triplex-forming and recombinagenic technology is developed to remediate the underlying genetic causes for diseases, such as hemoglobinopathies, and has a well-positioned technology profile and potential for translational medicine.