T-cell activation is mediated not only by antigen stimulation through T-cell receptors but also by costimulatory signals through costimulatory molecules. Among several costimulatory molecules, the tumor necrosis factor (TNF) receptor family member OX40 plays a key role in the survival and homeostasis of effector and memory T cells. According to the conventional understanding of OX40 costimulation, an interaction between OX40 and OX40 ligand (OX40L) occurs when activated T cells bind to professional antigen-presenting cells (APCs). The T-cell functions, including cytokine production, expansion, and survival, are then enhanced by the OX40 costimulatory signals. Over the last half-decade, evidence has accumulated that OX40 signals are critical for controlling the function and differentiation of Foxp3 + regulatory T cells, indicating a new aspect of OX40-mediated autoimmunity. Furthermore, the expression of OX40L by mast cells was shown to be important for controlling inflammation through regulatory T-cell function. Besides the essential role played by OX40 signaling in generating memory CD4 T cells, recent reports show that it also has a unique role in generating memory CD8 T cells. In addition, recent genome-wide association studies have identified single-nucleotide polymorphisms of the OX40L and OX40 genes that are related to cardiovascular diseases and SLE, providing direct evidence for the involvement of the OX40-OX40L interaction in human diseases. Here, we review recent progress on how the OX40-OX40L interaction regulates T-cell tolerance, peripheral T-cell homeostasis, and T-cell-mediated inflammatory diseases.