Imaging mass spectrometry has emerged as a powerful tool to map the spatial distributions of lipid and metabolites in biological tissues. However, these analyses are challenged by the multitude of isobaric (i.e., same nominal mass) and isomeric compounds present in most samples. Failure to adequately separate these compounds results in inaccurate or incomplete chemical identifications and produces composite images of spatial distribution arising from multiple compounds. A number of techniques have been developed to more completely resolve and identify this complex chemical milieu. These include methods that rely on condensed-phase chemical derivatization and gas-phase ion chemistry, or some combination thereof. This Young Scientist Feature focuses on summarizing the analytical figures of merit of these tools, highlighting their relative speeds, limits of detection, molecular specificities, and eases-of-use. It will also include current challenges and future perspectives for resolving structural isomers in imaging mass spectrometry experiments.