OX4 (CD134) and its binding partner, OX4L (CD252), are members of the tumor necrosis factor receptor/tumor necrosis factor superfamily, is known to break an existing state of tolerance in malignancies, leading to a reactivation of antitumor immunity. The interaction between OX4 and OX4L plays an important role in antigen-specific T-cell expansion and survival. OX4 and OX4L also regulate cytokine production from T cells, antigen-presenting cells, natural killer cells, and natural killer T cells, and modulate cytokine receptor signaling. In line with these important modulatory functions, OX4-OX4L interactions have been found to play a central role in the development of multiple inflammatory and autoimmune diseases, making them attractive candidates for intervention in the clinic. Conversely, stimulating OX4 has shown it to be a candidate for therapeutic immunization strategies for cancer and infectious disease.