This critical review analyzes the behavior of natural and synthetic polyampholytes and current theoretical descriptions based on Coulomb interactions between complementary charges. Sequences of bonds and groups that occur between fixed charges display interactions with other groups along the chain, or with solvent components, which may antagonize the behavior expected from intramolecular Coulomb attraction. The relevant thermodynamic description of charge-independent interaction is also reviewed. The relationship between the various interactions hinges on the problem of the intra and intersupramolecular stabilization of biomacromolecules. Two results of the analysis of polyampholytes are, however, enlightening the complex problem. One is the verification that the basic predictions of current polyampholyte theory conform to selected aspects of the experimental behavior. The other is the astonishing variety of supramolecular structures and transformation exhibited by polyampholytes when hydrophobic and other non-charge dependent interactions are operative.