OX40 (CD134) is a tumor necrosis factor (TNF) receptor expressed primarily on activated CD4⁺ and CD8⁺ T cells and transmits a potent costimulatory signal when engaged. OX40 is transiently expressed after T‐cell receptor engagement and is upregulated on the most recently antigen‐activated T cells within inflammatory lesions (e.g. sites of autoimmune destruction and on tumor‐infiltrating lymphocytes). Hence, it is an attractive target to modulate immune responses: OX40 blocking agents to inhibit undesirable inflammation or OX40 agonists to enhance immune responses. In regards to this review, OX40 agonists enhance anti‐tumor immunity, which leads to therapeutic effects in mouse tumor models. A team of laboratory and clinical scientists at the Providence Cancer Center has collaborated to bring the preclinical observations in cancer models from the bench to the bedside. This review describes the journey from in vitro experiments through preclinical mouse models to the successful translation of the first OX40 agonist to the clinic for the treatment of patients with cancer.