Aggressive B-cell non-Hodgkin lymphoma (aNHL) accounts for ∼50% of all NHL cases. The only potentially curative, broadly available treatment for patients with relapse, failing frontline treatment, is high-dose therapy followed by autologous stem cell transplantation (ASCT); patients ineligible for/who have failed ASCT have limited standard-of-care options. We conducted a structured review of treatments for relapsed/refractory patients with aNHL based on literature published between 2006 and 2017. Of the 22 publications identified for inclusion, most described phase II, single-arm trials ( = 25-217), and only three were randomized studies (phase II [ = 96], phase II/III [ = 111] and phase III [ = 338]). The majority of treatments evaluated resulted in only modest efficacy (median progression-free survival, 2.1-20.0 months) and ultimately poor health outcomes (median overall survival, 25 weeks-15.5 months). In conclusion, there is an unmet need for novel, effective, and tolerable treatments for patients with relapsed/refractory aNHL who are ineligible for/have failed ASCT.