Introduction: Even after recent advancements with monoclonal antibodies, antibody drug conjugates and immune therapies, relapsed and refractory lymphomas remain challenging to treat; and the definition and treatment approaches of hard-to-treat lymphomas (HTL) continue to evolve. Areas covered: In this review, we will address HTL encompassing diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL) and peripheral T cell lymphomas (PTCL). DLBCL, which comprises 30–40% of non-Hodgkin lymphomas is a highly aggressive and heterogeneous malignancy, with primary refractory or relapsed disease remaining a therapeutic challenge. Similarly, early relapse within 2 years of primary treatment in the more indolent FL is associated with inferior outcomes. Finally, PTCL are universally aggressive and carry a poor prognosis. Expert commentary: Recently, novel antibodies, antibody drug conjugates, immunotherapies and cellular therapy (CAR therapy) have shown promising results in early phase clinical trials. These agents are changing the landscape of treatment of lymphomas and will be extremely important for improving outcomes of HTL. Importantly, revising current strict eligibility criteria for clinical trial participation is needed to help these patients benefit from these novel agents.