Paradigms of protein tyrosine kinase (PTK)-mediated immunoreceptor signalling have developed largely from studies of molecules containing immunoreceptor tyrosine-based activation motifs (ITAM) and immunoreceptor tyrosine-based inhibition motifs (ITIM). In some circumstances, ITAM can mediate inhibition and ITIM can propagate activation signals. In addition to classical immune cells, some ITAM- and ITIM-encoding proteins are more widely expressed and are crucial to the development of haemopoietic cells, like osteoclasts and natural killer cells, as well as tissues such as bone and brain. Closer analysis of activating proteins reveals that some potentially encode ITIM within an ITAM. These 'closet' ITIM could, under conditions of partial ITAM phosphorylation, mediate inhibitory signalling.