Hepatocellular carcinoma (HCC) is the most prevalent type of liver cancer and the third leading cause of cancer deaths worldwide. Current therapies for advanced HCC, including sorafenib, are suboptimal, in part due to patient inter- and intra-tumor heterogeneity. Approaches that systematically identify drivers or suppressors of liver cancer could help identify therapies to individualize treatment or to prevent HCC. In these studies, I aimed to annotate gene function by employing innovative approaches with CRISPR interference (CRISPRi) and CRISPR activation (CRISPRa) screens in mouse livers to identify genes with a role in liver cancer and to perform mechanistic studies on NR1H3, a candidate gene encoding for LXRα, arising from a cDNA screen performed previously in our laboratory. For the CRISPR-based screens, I delivered a guide RNA (gRNA) library targeting genes of interest on plasmids that contain Myc coding sequence to drive hyperproliferation in hepatocytes. The CRISPRi gRNA library targeted genes that are known targets of FDA-approved drugs and the CRISPRa gRNA library targeted genes frequently amplified and upregulated in HCC patients. The CRISPRi screen identified Smn1 as a potential driver of liver hyperproliferation. Validation and mechanistic studies are required to understand the potential of this gene as a target for therapy in the clinic. Most notably, in the CRISPRa screen, gRNA sequences specific to Vps72, Mrpl9 and Gba were detected in multiple tumors, implicating a role in liver tumorigenesis. Plasmids containing Myc, CRISPRa components, and a single gene-targeting gRNA demonstrated that Vps72, Gba, and Mrpl9 accelerate MYC-driven tumorigenesis and decrease survival. These studies established a novel model of liver cancer that combines the Myc oncogene with a CRISPRa system to annotate driver genes in human HCC. Additionally, we showed that LXR agonism in combination with sorafenib effectively kills HCC cells in vitro through downregulation of the cell cycle and upregulation of markers of apoptosis. Overall, we identified several promising targets for the treatment of HCC, with potential to impact on the care of patients at risk of developing HCC.