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The clustered regularly interspaced short palindromic repeats (CRISPR)-Cas system of bacteria has furnished programmable nucleases (e.g., Cas9) that are transforming the field of genome editing with applications in basic and biomedical research, biotechnology, and agriculture. However, broader real-world applications of Cas9 require precision control of its activity over dose, time, and space as off-target effects, embryonic mosaicism, chromosomal translocations, and genotoxicity have been observed with elevated and/or prolonged nuclease activity. Here, we review chemical and optical methods for precision control of Cas9's activity.