Not many treatment options exist for patients with relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma (NHL) in whom first- and second-line therapies were unsuccessful. This is especially true for patients with aggressive lymphomas. The innovative agent pixantrone has shown some promising results in terms of disease-free and overall survival, both in monotherapy as well as in combinations. However, recent trials (Phase III and real-world studies) reported unsatisfactory results, thereby raising the question about the role of pixantrone in the current treatment of R/R aggressive lymphomas. Nonetheless, there might still be a potential position for this drug in combinations, for use as first-line treatment of patients with cardiac dysfunction. This article summarizes the definition, structure, mechanism of action and reduced cardiotoxicity of pixantrone as well as efficacy and toxicity both in monotherapy and in combinations, as treatment for aggressive and indolent non-Hodgkin lymphomas.