Although the crystalline S-layer arrays that form the exoskeleton of many archaea and bacteria have been studied for decades, a long-awaited crystal structure coupled with a growing understanding of the S-layer assembly process are injecting new excitement in the field. The trend is amplified by computational strategies that allow for in silico design of protein building blocks capable of self-assembling into 2D lattices and other prescribed quaternary structures. We review these and other recent developments toward achieving unparalleled control over the geometry, chemistry and function of protein-based 2D objects from the nanoscale to the mesoscale. © 2013 Elsevier Ltd.