Changes in the formulation of pigments and paint binders and the presence of additives used in the history of painting can complicate the interpretation of analytical data and may influence the characterization of the materials used in artworks. The limitations of the common analytical tools used to identify potential paint components including metallic driers, pigments, and the inorganic substrates of lake colors may also make analysis more difficult. X-Ray Fluorescence (XRF) spectroscopy is a common non-destructive technique used to collect inorganic elemental information from artworks. Advancements in XRF technology now permit the gathering of data from multi-layered paint systems and scanning technology can help characterize pigments across the entire surface of an artwork. These tools require an even greater understanding of the potential materials in an artwork to avoid misinterpretation of the data. The authors tested XRF’s ability to characterize lead, manganese, and cobalt driers. The presence of metallic driers could have an impact on the interpretation of the inorganic components in paint films. Lake pigment substrates often contain aluminum, tin, and calcium salts. The detection of these ions was also studied. Finally, the XRF detection of aluminum in lapis lazuli samples was assessed. These three groups of materials were also mixed with driers and/or other pigments to determine whether the presence of additional metal ions inhibited the detection of the characteristic elements. The authors used a Bruker ArtTax Micro XRF and a handheld Bruker Tracer III-SD XRF unit with and without a vacuum or helium purge for these experiments.