Recent work by a number of groups has highlighted the emerging potential associated with the marriage of nanoscale electronics and biological structure. Many biological macromolecules have evolved into structures typically primed for highly-specific surface recognition, analyte binding and, in some cases, facile and directional electron tunnelling. The redox-active centres of metalloproteins, for example, play a central role in photosynthesis and respiration and much progress has been made in constructively interfacing these moieties to man-made surfaces. Specifically, a variety of methodologies can be applied that not only facilitate controllable electronic coupling to underlying metallic electrode surfaces but also a highly spatially-resolved analysis of the (potentially switchable) tunnel transport characteristics. Developments in our understanding and manipulation of these entities at a molecular level has further led us to the point where nanobiotechnological advances can be realistically proposed. Strategies to exploit combined advanced lithography and molecular manipulation methods are described. Recent protein tunnel transport experiments in proximal probe junctions are discussed. In a CP-AFM metal-protein-metal tunnel junction experimental data in the low voltage regime is well-described by a non-resonant charge transfer process in which the protein matrix is modelled as a uniform tunnel barrier, the absolute magnitude of which can be controllably modulated by compressional force. Comparative analysis within STM-based junctions of metal substituted metalloproteins are additionally supportive of transport being dominantly non-resonant. Recent progress in interfacing the unique properties of nanoscale electrical junctions to biological structure, more generally, is reviewed herein. © The Royal Society of Chemistry 2005.