All of the research and development in the field has translated to considerable increase in commercial interest in CRISPR based diagnostics and therapeutics over the last few years. Currently there are >140 CRISPR-based therapeutics in various stages of clinical trials a quarter of which appear to be for a range of cancer subtypes. Despite the great strides that have occurred in this field, there remain quite a few challenges in using CRISPR/Cas technology for therapeutic purposes. Researchers are actively engaged in developing alternative and better approaches to overcome these limitations. Off-target effects of CRISPR/Cas technology are being addressed by the development of chemically modified gRNAs, high-fidelity nuclease variants, and controlled expression of genome editor nucleases. The PAM sequence requirement of SpCas9 restricts the scope of targetable genomic sites, however this issue can be addressed using engineered variants of Cas9 with alternative or relaxed PAM requirements or other naturally derived Cas9 orthologs, and Cas12a enzymes. Second-generation CRISPR based technologies such as base editing or prime editing enable the introduction of precise modifications independently of DSBs. Newer packaging and delivery methods like electroporation/nucleofection and lipid nanoparticles have great potential to overcome existing targeted delivery problems. The ongoing refinement of existing CRISPR components continue to improve the efficiency and specificity of CRISPR based therapeutics. Expanding the targeting capabilities and optimizing delivery systems continue to aid in significant improvements in clinical outcomes. Ultimately, in the future CRISPR based therapeutics are likely to be developed successfully for myriads of diseases beyond cancer. (accessed 2024 October 25th). ( ) MHRA authorises world-first gene therapy that aims to cure sickle-cell disease and transfusiondependent β-thalassemia. 2023. (accessed 2024 October 25th).