The CRISPR-Cas9 genome-editing technology, a powerful tool for addressing genetic disorders, faces significant challenges due to its potential off-target effects, which can lead to unwanted genetic modifications and diminish its therapeutic potential. This review summarizes recent advancements aimed at reducing these off-target effects. Key methods include optimizing sgRNA specificity through GC content, length, and chemical modifications, developing improved Cas9 variants like eSpCas9 and SpCas9-HF1, employing CRISPR nickase to reduce double-strand breaks, and utilizing prime editing, which does not require donor DNA or double-strand breaks. Additionally, anti-CRISPR proteins and the discovery of SuperFi-Cas9, a highly specific Cas9 variant, offer further strategies to enhance specificity. These advancements collectively aim to improve the precision and safety of CRISPR-Cas9 genome editing, making it more viable for clinical applications.The CRISPR-Cas9 genome-editing technology, a powerful tool for addressing genetic disorders, faces significant challenges due to its potential off-target effects, which can lead to unwanted genetic modifications and diminish its therapeutic potential. This review summarizes recent advancements aimed at reducing these off-target effects. Key methods include optimizing sgRNA specificity through GC content, length, and chemical modifications, developing improved Cas9 variants like eSpCas9 and SpCas9-HF1, employing CRISPR nickase to reduce double-strand breaks, and utilizing prime editing, which does not require donor DNA or double-strand breaks. Additionally, anti-CRISPR proteins and the discovery of SuperFi-Cas9, a highly specific Cas9 variant, offer further strategies to enhance specificity. These advancements collectively aim to improve the precision and safety of CRISPR-Cas9 genome editing, making it more viable for clinical applications.