Cutaneous T-cell lymphoma is a form of non-Hodgkin lymphoma that manifests initially in the skin and disseminates systemically as the disease progresses. Mycosis fungoides and Sézary syndrome are the most common subtypes of cutaneous T-cell lymphoma. Advanced mycosis fungoides and Sézary syndrome are life threatening with few treatment options. We searched for new agents by high-throughput screening of selected targeted compounds and identified high-value targets, including phosphatidylinositol 3-kinase (PI3K) and cyclin-dependent kinases. To validate these hits from the screen, we developed patient-derived xenograft mouse models that recapitulated the cardinal features of mycosis fungoides and Sézary syndrome and maintained histologic and molecular characteristics of their clinical counterparts. Importantly, we established a blood-based biomarker assay using tumor cell-free DNA to measure systemic tumor burden longitudinally in living mice during drug therapy. A PI3K inhibitor, BKM120, was tested in our patient-derived xenograft model leading to disease attenuation and prolonged survival. Isoform-specific small interfering RNA knockdowns and isoform-selective PI3K inhibitors identified PI3K-δ as required for tumor proliferation. Additional studies showed a synergistic combination of PI3K-α/δ inhibitors with histone deacetylase inhibitors. The strong preclinical efficacy of this potent combination against multiple patient-derived xenograft models makes it an excellent candidate for further clinical development.