Studies of molecular evolution at the protein structure level permit the identification of fundamental mechanisms that shape protein function in its broadest definition (catalyzed chemical reaction, interacting partners, and cellular localization). To be functional, most proteins assemble into macromolecular complexes following an ordered sequence of events. In this paper, Marsh and colleagues describe, for the first time, the intimate relationship between pathways of protein assembly, quaternary structure, and gene fusion in heteromeric complexes. This research shows a new perspective on gene fusion that will permit a better interpretation of fusion-based predictions. Moreover, the authors provide fundamental evidence to be considered in any future attempt of protein engineering based on gene fusion strategies.