Although misfolding of the cellular prion protein PrP(C) into an alternative form, denoted PrP(Sc), is a key event in prion infections, the normal function of PrP(C) remains to be clearly defined. Many PrP(C)-binding proteins have been identified, but authentication of these interactions in functional assays is incomplete. Doppel (Dpl), a recently discovered PrP-like protein, might provide a new avenue by which to explore physiological and pathological functions of PrP. For example, overexpression of Dpl causes apoptotic cerebellar cell death that is abrogated by PrP(C), indicating that these two proteins can act in a common pathway. Despite our incomplete understanding of PrP(C), immunological targeting of this PrP(Sc) precursor has produced encouraging results, indicating a potential point of intervention against these fatal diseases.