Significance Semi-invariant natural killer T (iNKT) cells are innate-like lymphocytes that control a variety of immune functions. iNKT cell functions are mediated by high-affinity interactions with self-agonists displayed by the lipid-presenting CD1d molecule. How iNKT cells attain tolerance to high-affinity interactions with self remains unknown. This understanding is of immunologic import, as an unbridled iNKT cell-mediated response can cause inflammatory diseases. We discovered that Nur77—a transcription factor expressed at high levels in iNKT cells—induced caspase-3–mediated apoptosis and markers of T cell exhaustion such as PD-1 in iNKT cell precursors, which led to hyporesponsiveness to a high-affinity lipid agonist. Thus, Nur77 plays a central role in self-tolerance induction of iNKT cells.