This chapter reviews landmark clinical trials that have shaped the management of hematologic malignancies and cancer-associated conditions, highlighting the transition from traditional cytotoxic regimens to targeted therapies, immunotherapies, and modern anticoagulation strategies. Trials such as ECOG 1484 established the role of consolidative radiotherapy in intermediate-grade non-Hodgkin lymphoma, while CLOT defined low-molecular-weight heparin as the standard for cancer-associated thrombosis. The RE-LY and AMPLIFY trials drove the adoption of direct oral anticoagulants, replacing warfarin as first-line therapy for atrial fibrillation and venous thromboembolism. The 4 T score validation study provided a reliable diagnostic tool for suspected heparin-induced thrombocytopenia, improving diagnostic stewardship. The IRIS trial revolutionized chronic myeloid leukemia treatment with imatinib, the first successful targeted therapy, setting the stage for tyrosine kinase inhibitor–based care. In solid tumors, ECOG E2100 illustrated both the promise and limitations of anti-VEGF therapy in breast cancer, leading to regulatory reevaluation. The KEYNOTE-024 trial ushered in immunotherapy as frontline treatment for PD-L1–high non-small-cell lung cancer, while the TOPPS trial clarified transfusion strategies in hematologic malignancies. Finally, ALCYONE established daratumumab-based combination therapy as a new standard for transplant-ineligible multiple myeloma. Collectively, these trials demonstrate the evolution of hematology/oncology from cytotoxic and supportive strategies toward precision medicine and immunotherapy, emphasizing the importance of evidence-based practice and ongoing clinical trial participation to refine patient care.