Click and bio-orthogonal reactions are dominated by cycloaddition reactions in general and 1,3-dipolar cycloadditions in particular. Among the dipoles routinely used for click chemistry, azides, nitrones, isonitriles, and nitrile oxides are the most popular. This review is focused on the emerging click chemistry that uses mesoionic compounds as dipole partners. Mesoionics are a very old family of molecules, but their use as reactants for click and bio-orthogonal chemistry is quite recent. The facility to derivatize these dipoles and to tune their reactivity toward cycloaddition reactions makes mesoionics an attractive opportunity for future click chemistry development. In addition, some compounds from this family are able to undergo click-and-release reactions, finding interesting applications in cells, as well as in animals. This review covers the synthetic access to main mesoionics, their reaction with dipolarophiles, and recent applications in chemical biology and heterocycle synthesis.