Zinc-finger nucleases (ZFNs) are powerful tools for editing the genomes of cell lines and model organisms. Given the breadth of their potential application, simple methods that increase ZFN activity, thus ensuring genome modification, are highly attractive. Here we show that transient hypothermia generally and robustly increased the level of stable, ZFN-induced gene disruption, thereby providing a simple technique to enhance the experimental efficacy of ZFNs.