Treating unfit patients with aggressive B-cell lymphoma poses the dilemma of balancing potential cure while minimizing toxicity because of frailty and comorbidities. Age greater than 80 years and common comorbidities such as cardiovascular disease and poorly controlled diabetes mellitus often preclude the use of full-dose anthracyclines and steroids, the backbones of standard regimens for aggressive B-cell lymphomas. Assessing patient fitness remains subjective, with no consensus on best practice or how to integrate assessment tools into decision making. Incorporation of prephase steroids for all unfit patients may markedly improve performance status with consideration of standard dose therapy, especially in patients less than age 80. Although randomized studies are lacking, current data suggest patients age ≥ 80 years are considered unfit a priori and should receive dose-reduced anthracycline regimens or anthracycline-free regimens. Severe toxicity is highest after the first cycle of chemotherapy. Dose reductions for cycle 1 in unfit patients with plans to escalate as tolerated is often an effective strategy. Unfit patients often benefit from comanagement with gerontologists, cardio-oncologists, and endocrinologists depending on age and the nature of comorbidities. Palliative therapy for patients with newly diagnosed aggressive B-cell lymphoma results in median survivals of less than 3 months, and in general, should only be considered in patients with untreatable comorbidities such as advanced dementia or refractory metastatic solid tumors. Incorporating new, potentially less toxic agents such as novel antibodies, antibody-drug conjugates, and bispecific antibodies into first-line therapy is an exciting future direction with potential for substantial benefit in less fit patients.