Significance: Hematological malignancies represent the fourth most diagnosed cancer. Relapse and acquired resistance to anticancer therapy constitute two actual issues that need to be overcome. Nitric oxide (NO) plays a pivotal role in regulating cancer progression. At present, many studies are attempting to uncover the potentials of modulating NO levels to improve the efficacy of currently available treatments against lymphoma, leukemia, and myeloma. Recent Advances: It is becoming progressively clear that NO modulation may help hematological cancer management, either by targeting directly tumor cells or by driving the immune system to eliminate cancer cells. Critical Issues: NO is a dual molecule that can have a tumor-protecting or stimulating effect, depending on its local concentration. Moreover, NO is able to target a wide range of molecules involved in both cancer genesis and evolution. In this review, an overview of the recent findings regarding the pivotal role played by NO and nitric oxide synthase in cancer progression and anticancer therapy is presented, with particular focus on hematological malignancies. Future Directions: It is critical to establish the cancer-specific function of NO and critically drive its modulation to improve cancer management toward a personalized approach. This has a special importance in hematological tumors, where the urgency of finding eradicative therapies is constant.