Nr4a1–3 encode a small family of orphan nuclear hormone receptors with transcriptional activity. Their expression reflects both acute and chronic antigen-receptor signaling in T and B-cells, and they have been implicated in critical aspects of lymphocyte development, tolerance, and function. These include roles in regulatory T-cell (Treg), thymic-negative selection, humoral responses, anergy, and exhaustion. Here, we review recent advances in this field such as functional roles in B-cells, transcriptional targets, and mechanism of action. We highlight recurrent themes, including integration of antigen-receptor signaling with costimulatory input, as well as unanswered questions and translational applications of this work.