A new treatment algorithm for patients with R/R LBCL after first-line therapy is proposed. Patients with refractory or relapsed disease within 1 year of completion of initial therapy should be considered for second-line CAR T-cell therapy (axi-cel or liso-cel) if eligible. Patients who relapse >1 year from initial therapy should be considered for ASCT if transplant-eligible. Patients who are not eligible for second-line cellular therapy have numerous therapeutic alternatives, including investigational agents/clinical trials. Selection of therapy should be individualized based upon disease and patient characteristics, treatment goals, patient preference, and logistical factors (some agents may only be indicated for third-line therapy and beyond). At the time of publication, no CAR T-cell therapy has yet been approved by the regulatory agencies for second-line therapy, but regulatory review is ongoing. Percentages are estimated and projected based upon data from clinical trials and historical outcomes. The dashed arrows indicate treatment path for patients who are not cured by cellular therapy. 1L, first-line; 2L, second-line; 3L+, third-line and beyond; ASCT, autologous stem cell transplantation; axi-cel, axicabtagene ciloleucel; BR, bendamustine and rituximab; CAR T-cell, chimeric antigen receptor T-cell therapy; LBCL, large B-cell lymphoma; liso-cel, lisocabtagene maraleucel; XRT, radiation therapy. Professional illustration by Somersault18:24.