Antigen receptor signaling in lymphocytes has been clearly implicated in the pathogenesis of the rheumatic diseases. Here, we review evidence from mouse models in which B-cell and T-cell signaling machinery is perturbed as well as data from functional studies of primary human lymphocytes and recent advances in human genetics. B-cell receptor hyper-responsiveness is identified as a nearly universal characteristic of systemic lupus erythematosus in mice and humans. Impaired and enhanced T-cell receptor signaling are both associated with distinct inflammatory diseases in mice. Mechanisms by which these pathways contribute to disease in mouse models and patients are under active investigation.