Changes in protein expression levels and protein structure may indicate genomic mutations and may be related to some diseases. Therefore, the precise quantification and characterization of proteins can be used for disease diagnosis. Compared with several other alternative methods, surface-enhanced Raman scattering (SERS) spectroscopy is regarded as an excellent choice for the quantification and structural characterization of proteins. Herein, we review the main advance of using plasmonic nanostructures as SERS sensing platform for this purpose. Three design approaches, including direct SERS, indirect SERS, and SERS-encoded nanoparticles, are discussed in the direction of developing new precise approaches of quantification and characterization of proteins. While this Review is focused on proteins, in order to highlight concepts of SERS-based sensors also detection of other biomolecules will be discussed.