Functional genomics is the discipline in molecular and cellular biology field that studies how genes and pathways contribute to a particular disease phenotype. Functional genomic screens are key in target discovery and hold the promise to enable the identification of drug targets with improved clinical attrition rate. The long-term success of target discovery and validation is currently based on four key pillar areas that will be reviewed in this chapter, including: (i) the creation and implementation of successful array screening modalities to perturb individual gene and protein functions in disease relevant models, (ii) the use of translatable and physiologically relevant models that mimic a particular disease phenotype and can be adapted to the screening throughput, (iii) the integration of complex assay readouts to interpret the biological outputs of cellular models upon perturbation, and (iv) the establishment of bioinformatic pipelines to enable quantitative analysis of phenotypic readouts resulting from genetic and
non-genetic perturbations.