Abstract: To reduce attrition rates during the drug discovery pipeline, there is increasing impetus to identify high quality targets for the initiation of drug discovery campaigns. Targets will have more chance of success if they carry genetic associations linking them to disease traits of interest with chances further improved if they show experimental evidence of tractability. Here we demonstrate the combinatorial use of chemogenomic and functional genomic screening technologies in complex primary immune cell models representing differing disease states. We have developed semi-automated 384-well high throughput arrayed CRISPR and chemogenomic screening methodologies in primary human macrophages, T-cells and B-cells. We have further employed a wide variety of phenotypically relevant readouts including cytokine release, transcriptional profiling, multi-dimensional flow cytometry and high content imaging. The gene lists explored in these screens were informed by human genetic data directly linking them to relevant disease traits of interest. Combining both chemogenomic and functional genomic screening technologies in primary translatable cellular assay systems should enable the identification of better targets to initiate drug discovery campaigns with a higher probability of success for clinical translation.