Precision medicine refers to the tailoring of medical management to the individual patient. Despite the advent of increasingly high-dimensional diagnostic tools and the enormous expansion of our therapeutic arsenal, precision medicine remains a promise rather than reality for most patients. A major factor responsible for making the realization of precision medicine challenging is the lack of a mechanistic understanding of how given biological variables impact the course of a disease. This work describes five studies which tackle different facets of precision medicine: in the first study, we report preclinical and clinical data of a novel therapeutic approach to harness a patient’s immune response to cancer by targeting suppressive immune cells in the tumor microenvironment (TME). The pharmacologic activation of Liver-X-receptor transcription factors led to depletion of immunosuppressive myeloid-derived suppressor cells in an APOE- dependent manner. The resulting unleashing of anti-tumor T cell immunity represents a novel myeloid cell-targeting approach for cancer immunotherapy. In studies two and three, we established APOE genotype as a potential biomarker to predict outcome in melanoma and COVID-19. Using mice bearing distinct human APOE variants, we found that the Alzheimer’s disease predisposing APOE4 variant enhances anti-melanoma immunity, while APOE2 dampens it. Interestingly, in COVID-19, we found that both APOE4 and APOE2 causally mediate detrimental outcomes. These discrepant phenotypic patterns can likely be explained by the pleiotropic roles of APOE, which we determined to include modulation of antiviral immunity and viral infection in the case of SARS-CoV-2 infection. In the fourth study, we investigated the potential role of uric acid levels as a biomarker for acute graft versus host disease. Finally, in the fifth study we dissected cancer stem cells in myelodysplastic syndromes to identify targets for potential novel therapeutic approaches. We identified CLL1 to be expressed on MDS cancer stem cells, validating its potential as a target for future therapies. In sum, the work presented herein spans a precision medicine spectrum from disease prediction over target identification to therapeutic assessment of new targeted therapies. It contributes to addressing the need to elucidate the mechanisms underlying differential disease courses and treatment responses across patients to unlock precision medicine for all patients.