Inhibitory co-receptors downmodulate B-cell receptor (BCR) signalling by setting a signalling threshold that prevents overstimulation of B cells. Activation of these inhibitory co-receptors occurs by phosphorylation on their cytoplasmic inhibitory immunoreceptor tyrosine-based inhibition motifs (ITIMs), followed by recruitment of the tyrosine phosphatase SHP-1 or the lipid phosphatase SHIP, and depends on their association with the BCR. Recent evidence shows that B-cell signal inhibition is regulated by ligand binding of inhibitory receptors.