Throughout recent history scientists have struggled to elucidate the biochemical and biophysical mechanisms that guide the assembly of macromolecular structures. The early models of "sub-assembly" or "self assembly" attempted to explain how individual components could interact in a precisely regulated manner to form higher-ordered complex biological structures. Subsequent studies, using viral systems as assembly models, demonstrated how protein-protein and protein-nucleic acid interactions assist in lowering the thermodynamic barriers that typically disfavor assembly.Due to their simplicity, viruses provide an ideal system to investigate the biophysical mechanisms that drive the assembly of complex biological structures. Proper virion assembly requires numerous macromolecular interactions that proceed along an ordered morphogenetic pathway. While structural proteins are incorporated into the final product, morphogenesis is equally dependent upon scaffolding proteins, which are not included in the mature virion. Since the identification of scaffolding proteins in the bacteriophage P22, homologues have been discovered in many systems. Scaffolding proteins play multiple roles during morphogenesis by inducing protein conformational switches and lowering the thermodynamic barriers to promote virion assembly, while ensuring the efficiency and fidelity of the final product.