We present a novel dataset assessing the specificity of protein-protein interactions between 69 transmitter and receiver domains from two-component system (TCS)-signalling pathways. TCS require a conserved protein-protein interaction between partner transmitter and receiver domains for signal transduction. The complex prokaryote Myxococcus xanthus possesses an unusually large number of TCS genes, many of which have no obvious interaction partners. Interactions between TCS domains of M. xanthus were assessed using a yeast two-hybrid assay, in which domains were expressed as both bait and prey translational fusions. LacZ production was monitored as an indicator of protein-protein interaction, and the strength of interactions classified as weak, medium or strong. Two-hundred and fifty-five transmitter-receiver domain interactions were observed (46 strong), allowing identification of potential signalling partners for individual M. xanthus TCS proteins. In addition, the dataset provides interesting meta information. For instance, many strong interactions were identified between different transmitter domain pairs (34) and receiver domain pairs (23), suggesting a surprisingly large degree of heterodimerisation of these domains. Proteins in our dataset that exhibited similar profiles of interactions, often shared a similar biological function, suggesting that interaction profiles can provide information on biological function, even considering sets of homologous domains.