Targeted nucleases have recently emerged as a powerful genome editing tool. The ability of introducing targeted, desired changes into mammalian genome makes them an invaluable tool to unravel functions of miRN"s in biology and disease. In combination with homologous donor vector, targeted nucleases can achieve high efficiency and precision, enabling bi-allelic ablation of miRN" in cultured somatic cells. Here we review the structure and function of miRN" as well as the unique implementation of genome editing technology in modifying miRN" sequences in mammalians. This chapter discusses the four mainstay genome editing technologies meganuclease, zinc finger nuclease ZFN , transcription activator-like effector nuclease T"LEN and clustered regularly interspaced short palindromic repeat-associated nuclease Cas CRISPR-Cas , focusing on T"LEN.