Nuclease-based gene editing could be likened to hacksaw surgery upon the genome. In fact, two recent papers have reiterated the untoward consequences of CRISPR-Cas-mediated double-stranded breaks (DSBs): p53-induced toxicity and effects upon the gross morphology of chromosomes. Álvarez et al. identified genomic sites of high p53 toxicity that appear more frequently observed at specific euchromatin markers and also noted variable levels of ploidy when targeting specific sites. 1 Nahmad et al. report aneuploidy, the alteration of the chromosomal number, following CRISPR treatment at clinically relevant target sites in primary T cells. 2 Taken together, these studies suggest a linkage between genome access, p53 toxicity, and aneuploidy. Notably, there were no sites free from p53 toxicity, just those with lower and higher levels of susceptibility.