Cancer is a complex disease caused by the aberrant expression of many diverse gene products. Large sequencing studies have shed some light onto the nature of these cancer-causing aberrations, but many of the critical tumour driving pathways have not yet been discovered. Functional genetic screening approaches enable the identification of genes involved in the development of cancer. Therefore, we are employing genome wide CRISPR knockout and activation screening techniques in primary tumour prone haematopoietic stem and progenitor cells (HSPCs) in vivo. In Em-Myc lymphoma development we discovered the mTOR inhibitors NPRL3 and DEPDC5 of the GATOR1 complex as potent tumour suppressor genes. Further analysis revealed that these components are under control of the p53 tumour suppressor gene. Excitingly, GATOR1 component deleted Em-Myc lymphomas are highly susceptibility to the mTORC1 inhibitor rapamycin. To further delineate the complex genetic changes found in cancer, we are currently advancing our CRISPR screening toolbox and applying it to other tumour prone genetic backgrounds. Our results to date clearly demonstrate the power of unbiased functional genetic screens in vivo for identifying critical cancer drivers as potential prognostic markers or therapeutic targets in the clinic.