Large macromolecular assemblies are widespread in all cell types with diverse structural and functional roles. Whether localized to membranes, nuclei, or cytoplasm, multimeric protein–nucleic acid complexes may be viewed as sophisticated nanomachines, an inspiration to chemical design. The formation of large biological assemblies follows a complex and hierarchical self-assembly process via ordered molecular recognition events. Serving a paradigm for biological assembly, extensive past studies of T4 bacteriophage and bacterial ribosomes by many groups have been revealing distinct design strategies, yet these two very different multimeric complexes share common mechanistic motifs. An emerging biochip approach highlights two conceptual notions to promote the study of assembly pathways: cell-free expression provides coupling between synthesis and assembly; surface anchoring allows high-resolution imaging of structural intermediates and opens up opportunities for rewiring a network by defining unnatural scaffolds for synthetic design applications. WIREs Nanomed Nanobiotechnol 2013, 5:613–628. doi: 10.1002/wnan.1227

Conflict of interest: The authors have declared no conflicts of interest for this article.

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