The incorporation of silica nanoparticles into drug delivery vehicles, and other nanotech platforms, has experienced rapid and significant growth over the past decade. However, as these nanoparticle-based systems become more and more complex, the methods used to analyze these systems have evolved at a comparatively much slower pace, resulting in the need for researchers to expand their toolbox and devise new strategies to characterize these materials. This article describes how X-ray photoelectron spectroscopy (XPS) and time-of-flight secondary ion mass spectrometry (ToF-SIMS) were recently employed in the analysis of two separate drug delivery systems which contain organic compounds covalently attached to the surfaces of silica nanoparticles. These techniques provided a deluge of qualitative and quantitative information about these drug delivery systems, and have several clear advantages over more common characterization procedures such as Fourier transform infrared spectroscopy (FT-IR) and solid state nuclear magnetic resonance (SSNMR). Thus, XPS and ToF-SIMS should be an integral component of the standard characterization protocol for any nanoparticle-based assemblies-particularly silica-based drug delivery systems-as this field of research continues to develop.