The answer to: How did protein X evolve, is typically, via sequences changes in protein Y whose structure and function are closely related. But how did Y, and Y’s precursor, and Y’s precursor’s precursor, emerge? Some proteins emerged de novo, namely from a fundamentally different precursor, for example from a short segment grafted from a different fold. We are examining routes leading from relatively short polypeptides (25 -50 amino acids) to globular, functional proteins. We are particularly interested in ancient motifs that are common to many different enzyme families (e.g. enzymes belonging to the Rossmann fold) and that led to the emergence of the very first protein(s).