The FDA’s new draft guidance on safety assessment for human genome-editing therapies reflects increasing regulatory attention to off-target edits, chromosomal alterations, and sequencing-based approaches to safety evaluation. It gives a sense of the questions likely to shape the next stage of clinical development, particularly how unintended genomic effects are detected, interpreted, and weighed. As genome editing becomes more firmly embedded in medicine, documents of this kind can help to define what sufficiently rigorous preclinical safety evidence should look like. (https://www.fda.gov/media/191966/download)