Cyclic diguanlylate (cyclic di-GMP) is a second messenger utilized by many bacteria to control a variety of phenotypes, such as motility, biofilm formation, and virulence. In the genomes of these bacteria, a notably large number of genes are found to encode proteins that not only respond to cyclic di-GMP, but also numerous that synthesize and/or degrade the second messenger. A number of such genes that are associated with cyclic di-GMP signaling are located on mobile genetic elements (MGEs) including plasmids, integrative and conjugative elements, bacteriophages, genomic islands, and transposons. These MGEs facilitate horizontal transfer between bacteria, making cyclic di-GMP associated genes available to many different hosts. This is curious because genes that are part of complex systems are normally regarded as improbable to be transferred horizontally. Here the relationship between cyclic di-GMP signaling and horizontal gene transfer is examined. Many of the properties that make cyclic di-GMP signaling such an effective, energetically favorable, and diverse system for controlling multiple phenotypes, in addition to the modular nature of cyclic di-GMP associated genes, seems to make it uniquely fit for horizontal transfer. Effector proteins that respond to cyclic di-GMP levels should be able to enter a new genomic context with minimum disturbance as the cellular level of cyclic di-GMP is not affected. Contrarily, MGEencoded proteins that alter the level of cyclic di-GMP may have detrimental effects on host fitness. However, it is plausible that proteins that alter the levels of cyclic di- GMP are transferred if they only are expressed or activated in response to specific clues. Alternatively, such proteins may act by enforcing phenotypes that selfishly enhance the evolutionary success of the MGE.