Specific markers for diseases associated with protein aggregate depositions are of great interest. Here we report the use of conjugated polyelectrolytes as conformation-sensitive optical probes for histological labeling of amyloid deposits in ex vivo tissue samples-amyloid light chains in primary systemic amyloidosis, islet amyloid polypeptide in human pancreas, and Abeta amyloid in Alzheimer's disease. Under suitable conditions, these probes bind specifically to amyloid deposits, and this is seen as an orange-red emission from the polyelectrolyte. Furthermore, the probes emit light of different colors when bound to different amyloid deposits or other intracellular structures. This phenomenon is most probably due to differences in the protein conformation in these structures. Hence, different protein conformations will generate geometric alterations of the bound polyelectrolyte backbone, affording different emissions from the bound probe. Conformation-sensitive probes thus provide a direct link between spectral signal and protein conformation. Finally, the probes also proved useful for ex vivo fluorescence imaging by multiphoton excitation.