The function mediated by the engagement of the lymphocyte activation gene-3 (LAG-3, CD223) receptor expressed on activated T cells by its MHC class II ligand has remained enigmatic, partly owing to discrepancies between published results in human and mouse systems. Recent studies in mice have reconciled previous interpretations and clearly show that, as in human cells, LAG-3 negatively regulates T-cell function and homeostasis. As a soluble molecule, LAG-3 activates antigen-presenting cells through MHC class II signalling, leading to increased antigen-specific T-cell responses in vivo.