The study by Haapaniemi et al. reports that CRISPR/Cas9-mediated genome editing in p53-proficient cells induces a p53-mediated DNA damage response and cell cycle arrest, leading to reduced efficiency of homologous recombination (HR) and increased error-prone non-homologous end-joining (NHEJ). Transient inhibition of p53, either through the use of a p53 antagonist or by transient Cas9 activation, significantly improves the rate of HR and precision genome editing. However, this approach also makes cells transiently vulnerable to chromosomal rearrangements and other tumorigenic mutations. The authors caution that while transient p53 inhibition can enhance genome editing efficiency, it may also facilitate the selection of cells with potentially harmful mutations, particularly in the context of therapeutic applications. Future research should focus on understanding and controlling the DNA damage response induced by Cas9 to balance the benefits and risks of CRISPR/Cas9 in clinical settings.The study by Haapaniemi et al. reports that CRISPR/Cas9-mediated genome editing in p53-proficient cells induces a p53-mediated DNA damage response and cell cycle arrest, leading to reduced efficiency of homologous recombination (HR) and increased error-prone non-homologous end-joining (NHEJ). Transient inhibition of p53, either through the use of a p53 antagonist or by transient Cas9 activation, significantly improves the rate of HR and precision genome editing. However, this approach also makes cells transiently vulnerable to chromosomal rearrangements and other tumorigenic mutations. The authors caution that while transient p53 inhibition can enhance genome editing efficiency, it may also facilitate the selection of cells with potentially harmful mutations, particularly in the context of therapeutic applications. Future research should focus on understanding and controlling the DNA damage response induced by Cas9 to balance the benefits and risks of CRISPR/Cas9 in clinical settings.