 CRISPR-slash-Cas9 is a powerful gene editing tool that has been widely used to study genes, create genetically modified organisms, and conduct preclinical research into genetic diseases. Despite its potential, there are concerns about off-target activity, or when the Cas9 enzyme cuts DNA at unintended locations. This can lead to unwanted mutations and complicate the interpretation of results. In this article, we discuss how off-target activity occurs, detection methods, and strategies to reduce it. Improving off-target specificity will allow more accurate interpretation of genome editing data, making it easier to apply this technology in both basic and clinical settings. This article was authored by Xiao Huizheng, Louis YT, Xiao Gang Wang, and others.