Cyclic diguanosine monophosphate (c-di-GMP) is known to be an important signaling molecule that regulates the formation of bacterial biofilms. We demonstrate here by UV, CD, and NMR that it displays a surprising polymorphism that varies with the monovalent counterion and is consistent with the formation of a G-quartet structure in K+ and a stacked structure in Li+ or Na+. The ability of this rigid molecule to adopt different alignments may be important to its biological role.