We developed a new strategy to detect protein-DNA binding through surface enhanced resonance Raman scattering (SERRS). Silver-plated DNA and gold nanoparticle assemblies were used to identify sequence-specific and concentration-dependent binding of a DNA cytosine-C5-methyltransferase and the eukaryotic transcriptional regulator, TATA binding protein. Proteins were identified through specific Raman-active labels, and affinities observed correlate well with those determined by other methods. Raman-active labeling and interchangeable DNA sequences create a platform for versatile investigation of multiprotein complexes.