Discovery of prions—proteins that are able to convert between structurally distinct states, of which one or more is transmissible, led to the concept of “protein-based inheritance”. According to this concept, the formation of prion fibrils causes DNA-independent heritable traits in microorganisms. Recently, we described a new and unusual type of prion inheritance. We showed that the yeast prions [PIN⁺] and [SWI⁺], like classical genes, demonstrate complementary interaction that causes a phenotypic change in yeast cells. Here, we discuss the possible mechanisms of such polyprionic inheritance and the perspectives in the identification of prions in various organisms using universal proteomic approaches.