Surface enhanced Raman spectroscopy (SERS) is a powerful technique capable of probing single molecules with unprecedented detail for biophysical studies. Unfortunately, most currently used SERS substrates contain 7-108, stability to laser illumination, and good measurement reproducibility. We have recently extended this idea to include silver particles and nanoshells around the liposome component, both of which exhibit increased SERS enhancement over the gold nanoparticle on mirror substrate. Lastly, we are incorporating cytochrome c within the liposome component of these substrates and carrying out single molecule SERS of the freely-diffusing protein molecules in a cell-like environment.