Classical immunoreceptors like lymphocyte antigen receptors and Fc-receptors (FcR) are central players of the adaptive immune response. These receptors utilize a common signal transduction mechanism, which relies on immunoreceptor tyrosine-based activation motifs (ITAMs) present in the receptor complex. Upon ligand binding to the receptors, tyrosines within the ITAM sequence are phosphorylated by Src-family kinases, leading to an SH2-domain mediated recruitment and activation of the Syk or the related ZAP-70 tyrosine kinase. These kinases then initiate further downstream signaling events. Here we review recent evidence indicating that components of this ITAM-based signaling machinery are also present in a number of non-lymphoid or even non-immune cell types and they participate in diverse biological functions beyond the adaptive immune response, including innate immune mechanisms, platelet activation, bone resorption or tumor development. These results suggest that the ITAM-based signaling paradigm has much wider implications than previously anticipated.