Recently, understanding of many molecular interactions has progressed appreciably and cellular events once thought to be by-products of more important reactions or to be detrimental to cellular function are now known to be part of complex interactions of the cell with its environment. Numerous proteins can elicit differing effects depending upon post-translational modification events such as complex glycosylation and endoproteolytic cleavage or through binding co-factors including metal ions; the prion protein (PrP) is likely one such example. Its absolute requirement for pathogenesis has made the function of PrP an area of intense study but with apparently inconsistent results. This may, in part, stem from the ability of PrP to undergo different modifications to varying extents depending upon precise cellular circumstances. Specific modifications may promote altered association with binding partners resulting in apparent promiscuity of PrP interactions and activation of different signalling pathways, producing the diversity of functions suggested for this protein. This review discusses how modification of PrP by internal cleavage and metal ion co-ordination might influence, or be influenced by, signal transduction cascades.