Immune checkpoint blockers (ICB) reinvigorate the immune system by removing the molecular brakes responsible for the scarce activity of immune phenotypes against malignant cells. After having proven their remarkable role as monotherapy, combinations of anti-Programmed cell death 1 (PD-1)/Programmed death-ligand 1 (PD-L1) agents with cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibodies, chemotherapy and/or anti-angiogenic compounds provide unprecedented results and durable responses across a variety of tumour types. Nevertheless, the main drawbacks of ICB are represented by primary and acquired resistance, translating into disease progression, as well as by immune-related toxicities. In this sense, novel strategies to foster the immune system through its direct stimulation are being tested in order to provide additional clinical improvements in patients with cancer. In this scenario, the co-stimulatory molecule OX40 (CD134) belongs to the next generation of immune therapeutic targets. Preliminary results of early clinical trials evaluating OX40 stimulation by means of different agents are encouraging. Here we review the rationale of OX40 targeting, highlighting the combination of OX40-directed therapies with different anticancer agents as a potential strategy to foster the immune system against malignant phenotypes.© Author (s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ on behalf of the European Society for Medical Oncology.