HEL was one of the first proteins to be mapped antigenically using mAb, and panels of mAb have been used as a measure of antigenicity in order to study regulation of the immune response and the apparent 'antigenic structure' of HEL. These studies have confirmed the multideterminant hypothesis derived from pAb. However, although the entire surface of HEL is potentially antigenic, the mature immune response appears to be dominated by three functionally nonoverlapping antigenic regions, defined operationally by antibody complementation assays. Recent structural studies have confirmed the existence of three distinct epitope clusters. Functional epitopes, defined by immunoassays, are generally only a subset of the structural epitope, the 14-17 amino acid residues which contact antibody in the X-ray structure of the complex. An even smaller subset of 'critical residues', the 'energetic' epitope, may predominate the interaction energetically. Antibody complex formation with HEL is enthalpically driven, and is accompanied by an unfavorable entropy change. Mutations of either antibody or antigen which lower affinity appear to do so primarily by increasing dissociation rates, and also appear to be accompanied by entropy/enthalpy compensation. The current availability of six structurally defined antibody-lysozyme complexes presents excellent opportunities for comparative studies in order to understand the structural bases of affinity, specificity, and thermodynamic properties, as well as the interrelationships of functional, structural, and energetic epitopes.