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The last decade has seen the development of an unprecedented number of new technologies that are being applied to transform our understanding of disease and the subsequent success of drug discovery. The dramatic advances in DNA sequencing technology and the more recent advances in other‐omics technologies including transcriptomics, proteomics, and metabolomics are enabling the understanding of disease at the genetic and cellular level to identify new drug targets, and to identify new disease biomarkers to enable disease segmentation and patient stratification in the clinic. Advances in stem cell technology together with technologies that enable the creation of tissue organoids in the laboratory are allowing the creation of complex models of disease (Lancaster et al. 2013), which together with advances in imaging technology are enabling the drug discovery scientist to better understand the efficacy and safety of potential medicines in preclinical studies. The huge increases in computational power, together with advances in Artificial Intelligence and Machine Learning are allowing drug discovery scientists to extract greater knowledge from these large‐omics datasets, to improve the speed and quality of chemistry design and enable the design of improved clinical studies (Vamathevan et al. 2019). Perhaps, the most impactful of the many new technologies applied in drug discovery in the last decade has been the rapid adoption of CRISPR/Cas9 throughout the drug discovery pipeline to create engineered cellular and animal models of disease to enable the study of the role of new drug targets in disease, alongside the development of CRISPR as a medicine in it’s own right or as a key tool in the creation of cell therapy medicines. Taken together, these and other new technologies have impacted every drug discovery program to enable a better understanding of the role of the drug target in disease and the design of molecules more likely to be safe and efficacious in the clinic. Alongside this, a number of new therapeutic modalities are entering the clinic including antisense onligonucleotide, mRNA, protein, and gene and cell therapies which are leading to a situation where every target becomes amenable to therapeutic manipulation. Taken together, the ability of these technologies to improve our understanding of disease, to create safer medicines and to target those medicines to the patient population most likely to benefit from them is leading to an increase in the success of drug discovery. This has been seen in an increase in the number of new molecular entities approved by the FDA with over 40 new medicines being approved each year between 2011 and 2020 compared with an average of around 20 new medicines approved each year between 2001 and 2010 (Batta et al. 2020). A number of reports also describe an increase in success of drug discovery including a recent publication from colleagues in AstraZeneca. Through the implementation of a new research strategy at AstraZeneca in 2010, success from Candidate Selection to product launch has increased from 4% to 20% while 3 projects are now started in early discovery to deliver a Candidate Drug compared with 5 projects in earlier years (Morgan et al. 2018). While this represents a huge increase in drug discovery productivity, it remains the case that the majority of projects fail with the primary cause of failure in research being due to target validation and in the clinic a lack of efficacy in Phase II clinical studies. In both cases, the root cause of failure is that the hypothesis linking the drug target to disease was incorrect and significant efforts are underway in both academia and industry to continue to increase the level of confidence the drug target at the start of, and throughout a drug discovery program to further increase drug discovery success in all therapeutic areas. Throughout this book, authors will present examples of the application of CRISPR/Cas9 to identify novel drug targets, to understand the role of these targets in disease, and to create cellular and animal model systems to allow the development of new medicines more likely to succeed in the clinic. While we remain within the first decade following the discovery of the ability of CRISPR (clustered regularly interspersed short palindromic repeats)/Cas9 systems for the precise editing of mammalian genomes (Jinek et al. 2012; Cong et al. 2013; Mali et al. 2013), this technology has become embedded throughout drug discovery research (Fellmann et al. 2017). Throughout this book, authors will discuss the current use of CRISPR/Cas9 to facilitate the development of new medicines, as a medicine in its own right, and as a highly sensitive point of care diagnostic. However, we remain in the infancy of the application of this technology, and its potential to transform our understanding and treatment of disease remains huge.