Fibrolamellar carcinoma (FLC) is a rare liver cancer that primarily occurs in young adults and usually presents at advanced stages with no known risk factors or serum biomarkers. Owing to the intrinsic drug resistance of FLC tumors and the dearth of effective therapeutic options, this cancer is a disease of urgent unmet need. The majority of FLC patients harbor the hallmark DNAJB1-PRKACA (DP fusion), which is sufficient for tumor initiation and progression. Despite significant efforts toward drug discovery, including small molecule inhibitors of the DP chimeric protein, FLC therapies are not yet developed. Moreover, many of the key oncogenic pathways and effectors of DP fusion activity remain uncharacterized. To address this gap in the field, my doctoral research comprised a dual-pronged approach by interrogating long noncoding RNA LINC00473 as a downstream effector of the DP fusion and investigating RNA interference (RNAi) as a candidate therapeutic strategy for FLC. Multidisciplinary approaches revealed that LINC00473 is markedly elevated in patient tumors and that its expression is responsive to the DP fusion oncoprotein in FLC tumor epithelial cells. Loss- and gain-of-function methods demonstrated that LINC00473 suppresses apoptosis, increases FLC marker gene expression, and promotes FLC growth in cell-based and animal models of disease. LINC00473 also plays an important role in modulating FLC energetics by promoting glycolysis and altering mitochondrial activity. Overall, these data unveil LINC00473 as a crucial regulator of FLC pathogenesis. This study strongly supports its potential utility as a biomarker of DP fusion activity and as a candidate therapeutic target for FLC. To develop RNAi therapeutics for FLC, my studies determined that targeting the DNAJB1-PRKACA fusion junction with short-interfering RNAs (siRNAs) leads to the silencing of the chimeric oncoprotein. Using patient-derived xenograft tumors, I determined that siRNAs combined with clinically approved lipid nanoparticle drug delivery results in dramatic regression of tumor growth. This work serves to illustrate that siRNA-based precision medicine is a promising strategy for targeted FLC therapy. This dissertation provides a comprehensive and interdisciplinary body of research that establishes LINC00473 as one of the best-characterized oncogenes in FLC and encompasses the first preclinical application of RNA therapy for this devastating disease.