The importance of immunoreceptor tyrosine-based activation motif (ITAM)-coupled receptors in modulating signalling pathways downstream of other types of receptor is well established, but the mechanisms underlying this modulation are not known. Recent data suggest that calcium-dependent signalling downstream of ITAM-coupled receptors regulates the amplitude and functional outcomes of cytokine and TLR signalling. In this Opinion article, I describe a model whereby the intensity of ITAM-dependent signalling and the balance of calcium signals relative to other ITAM-mediated signalling pathways determines whether cellular responses to cytokines and TLR ligands are increased or inhibited. This model describes mechanisms that explain how ITAM-coupled receptors regulate heterologous signalling pathways.