Two-component systems (TCSs) are a large family of signalling pathways characterized by the successive transfer of phosphoryl groups between the histidine and aspartate residues of paired histidine kinase and response regulator proteins. With the availability of genome sequences for four genera of myxobacteria it has become possible to assess the genomic complements of myxobacterial TCS genes and to characterize features of their organization and evolutionary heritage. In this study we have compiled lists of the TCS genes within myxobacterial genomes and characterized their domain architecture, gene organization and evolutionary relationships. In order to provide an appropriate context for our conclusions, where possible we have compared myxobacterial TCSs with those found in 316 other completely sequenced bacteria. Myxobacteria have the largest number of TCSs of any organisms. An unusually low proportion of TCS genes are paired in myxobacterial genomes, and myxobacterial histidine kinases also seem to sense internal signals to an unusual degree. Phylogenetic evidence has allowed us to suggest homologous relationships of proteins across the myxobacteria, and it appears that myxobacterial TCS evolution has been dominated by duplications, gene rearrangements and changes in sensory domain complements. The systematic classification of the TCS proteins of the myxobacteria presented here should also provide a framework for future experimental studies on two-component regulation in these organisms.