Polyampholyte cryogels are a less considered subject in comparison with cryogels based on nonionic, anionic and cationic precursors. This review is devoted to physicochemical behavior, complexation ability and catalytic properties of cryogels based on amphoteric macromolecules. Polyampholyte cryogels are able to exhibit the stimuli-responsive behavior and change the structure and morphology in response to temperature, pH of the medium, ionic strength and water–organic solvents. Moreover, they can uptake transition metal ions, anionic and cationic dyes, ionic surfactants, polyelectrolytes, proteins, and enzymes through formation of coordination bonds, hydrogen bonds, and electrostatic forces. The catalytic properties of polyampholyte cryogels themselves and with immobilized metal nanoparticles suspended are outlined following hydrolysis, transesterification, hydrogenation and oxidation reactions of various substrates. Application of polyampholyte cryogels as a protein-imprinted matrix for separation and purification of biomacromolecules and for sustained release of proteins is demonstrated. Comparative analysis of the behavior of polyampholyte cryogels with nonionic, anionic and cationic precursors is given together with concluding remarks.