The striking multiplicity, signal input diversity, and output specificity of c-di-GMP signaling proteins in many bacteria has brought second messenger signaling back onto the agenda of contemporary microbiology. How can several signaling pathways act in parallel in a specific manner if all of them use the same diffusible second messenger present at a certain global cellular concentration? Recent research has now shown that bacteria achieve this by flexibly combining modes of local and global c-di-GMP signaling in complex signaling networks. Three criteria have to be met to define local c-di-GMP signaling: specific knockout phenotypes, direct interactions between proteins involved, and actual cellular c-di-GMP levels remaining below the Kd of effectors. Adaptive changes in signaling network architecture can further enhance signaling flexibility.