The experimental murine models offer unique opportunities to study the genetic, cellular, and molecular basis for variable immune responsiveness to HBV-encoded antigens. The mouse has provided a means of studying the immunogenicity of the pre-S regions of HBsAg and has elucidated the independent H-2-linked genes regulating antibody production to pre-S and S region determinants. The ability to circumvent genetic nonresponsiveness has implications for the design of future HBV vaccines. Mice also afforded the opportunity to examine the ability of HBcAg to activate B cells directly, and to prime Th cells capable of eliciting antibody to envelope proteins. These observations have potential clinical relevance, implications for vaccine design, and may explain the ability of HBcAg vaccination to protect against HBV infection. The murine system ha also facilitated the mapping of T-cell and B-cell recognition sites within HBV proteins, which at least conceptually enhances the prospects for development of a synthetic HBV vaccine. Antibody-binding sites appear to be similar in humans and mice; the extent to which their T-cell repertoires overlap is not known. However, the chemical and structural constraints imposed on T-cell antigenicity, and the fact that MHC-encoded class II molecules and the cellular mechanisms mediating T-cell recognition are conserved across species, make such overlaps appear likely. Furthermore, the ability to generate transgenic mice that express the various HBV proteins has yielded important insights into possible immunopathogenic mechanism and immunologic tolerance mechanisms that may predispose to chronic infection.