In genomics, the ability to amplify rare transcripts has enabled rapid advances in the understanding of gene expression patterns in human disease. The inability to increase the copy number and to detect the signal of rare proteins as unique species in biological samples has hindered the ability of proteomics to dissect human disease with the same complexity as genomic analyses. Advances in nanotechnology have begun to allow researchers to identify low-abundance proteins in samples through techniques that rely upon both nanoparticles and nanoscale devices. Coupled with rapid advances made in protein identification and isolation over the past decade, currently available technology enables more effective multiplexing and improved signal-to-noise, which enhances detection of low-abundance proteins in cellular and tissue lysates significantly. Techniques, including nanowires, nanocantilevers, bio-barcoding and surface-enhanced Raman spectroscopy, permit the detection of proteins into the low attomolar range, where many biologically important cellular processes occur. In this review, we summarize several such techniques, highlight their implementation in current protein research and comment on their potential role in future proteomic investigations and biomedical applications.