Drug attrition in clinical trials due to inaccurate preclinical target validation is a huge problem facing drug discovery. Drug candidates with adequate pharmacokinetics and safety margins still commonly fail, due to lack of efficacy. This suggests that often the ‘wrong’ target has been selected as the focus of the therapeutic program. Successful target validation will increasingly rely on the use of novel genetic and non-genetic tools including CRISPR and targeted protein degradation to disease relevant models. Combined with computational pathway analytics, testable hypotheses can be generated in an unbiased manner. This course will show how these technologies are being applied in the field of target validation in industry and academia and I will address how the integration of genome editing, targeted protein degradation and AI/ML/bioinformatic tools is impacting the search for newly validated targets. Finally, insights on how the use of these new tools in target validation might revolutionize the drug discovery paradigm will also be discussed.