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Abstract Telomeric DNA are TTAGGG tandem repeats, which are susceptible for oxidative DNA damage and hotspot regions for formation of DNA secondary structures such as t-loop, D-loop, G-quadruplexes (G4), and R-loop. In the past two decades, unique DNA or RNA secondary structures at telomeres or some specific regions of genome have become promising therapeutic targets. G-quadruplex and R-loops at telomeres or transcribed regions of genome have been considered as the potential targets for cancer therapy. Here we discuss the potentials to target the secondary structures (G4s and R-loops) in genome as therapy approaches.