This dissertation focuses on the application of diatom frustules, the biosilica shell of an algae possessing physical and photonic properties capable of enhancing optical signals, for the enhancement of optical sensing. In this work, we incorporate diatom frustules into biosensors for signal enhancement and improved target molecule detection. The potential for immunoassay improvement from frustules is first demonstrated using standard sandwich immunoassay fluorescence detection and various analytical methods are explored to analyze the signal. The diatom-based sandwich fluorescence immunoassay is then employed to the detection of the clinically important biomarker, N-terminal pro-B-type natriuretic peptide (NT-proBNP), for the screening of heart failure. Machine learning analyses are employed to further improve the results and enable efficient screening in human plasma. Lastly, the versatility of the frustules is demonstrated by utilizing the frustule, paired with a core-shell nanoparticle, to perform surface-enhanced Raman spectroscopy detection of vapors from explosives. This work validates the utilization of diatom frustules as a means of enhancing optical signals and highlights their unique capabilities to enable superior analyte detection.