Polyampholytes are charged macromolecules bearing both anionic and cationic groups along the polymer backbone. Polyampholytes can be synthesized by classic and controlled free radical polymerization, anionic polymerization, and group transfer polymerization (GTP). The aqueous solution behavior of polyampholytes is dictated by columbic interactions between the basic and acidic residues. Polyampholytes show both polyelectrolyte and anti-polyelectrolyte behavior in aqueous media. Factors such as charge density, charge asymmetry (i.e., degree of charge balance), charge spacing and distribution, substrate surface charge, structural conformation, and solution ionic strength are critical parameters. Polyampholytes are interesting for numerous reasons and are used for many technology processes such as water treatment, enhanced oil recovery (EOR), sludge dewatering, papermaking, pigment retention, mineral processing, and flocculation. In the present study, the main structural features, behaviors, mechanisms of interaction, and recent field applications of polyacrylamide (PAM)-based polyampholytes are reviewed.