The outcomes of Relapsed/Refractory (R/R) Diffuse Large B-cell lymphoma have been historically poor. The recent development of several novel therapies including CD19 directed agents has improved the prognosis of this disease significantly. Chimeric antigen receptor (CAR) T-cell therapy has drastically changed the treatment of R/R DLBCL, but it is still associated with significant barriers and limited access. Tafasitamab (an anti-CD19 engineered monoclonal antibody), in addition to lenalidomide, has shown significant efficacy with exceptionally durable responses in patients with R/R DLBCL who are ineligible for autologous stem cell transplantation (ASCT). Tafasitamab-lenalidomide and certain other therapies (ie, antibody-drug conjugates and bispecific antibodies) are important treatment options for patients who are ineligible for CAR-T due to co-morbidities or lack of access, and patients with rapid progression of disease who are unable to wait for manufacturing of CAR-T. This review will thus discuss currently approved and recently studied targeted treatment options for patients with R/R DLBCL with an emphasis on CAR-T alternative options, particularly Tafasitamab-lenalidomide.