Since a NanoSIMS high-resolution secondary ion mass spectrometry (SIMS) instrument was first used for cosmochemistry investigations over a decade ago, both interest in NanoSIMS and the number of instruments available have significantly increased. However, SIMS comes with a set of challenges that are of both technical and conceptual nature, particularly for complex samples such as soils. Here, we synthesize existing research and provide conceptual and technical guidance to those who wish to investigate soil processes at the submicron scale using SIMS, specifically with NanoSIMS. Our review not only offers advice resulting from our own operational experience but also intends to promote synergistic research on yet unresolved methodological issues. We identify and describe the basic setup of a NanoSIMS instrument, and important issues that may arise as a soil sample specimen are prepared for NanoSIMS analysis. This is complemented by discussions of experimental design, data analysis, and data representation. Next to experimental design, sample preparation is the most crucial prerequisite for successful NanoSIMS analyses. We discuss the requirements and limitations for sample preparation over the size range from individual soil particles to intact soil structures such as macroaggregates or intact soil cores. For robust interpretation of data obtained by NanoSIMS, parallel spatial, textural (scanning electron microscopy, atomic force microscopy), or compositional analyses (scanning transmission X-ray microscopy) are often necessary to provide necessary context. We suggest that NanoSIMS analysis is most valuable when applied in concert with other analytical procedures and can provide powerful inference about small-scale processes that can be traced via isotopic labeling or elemental mapping.