Covering: 2009-2019 Over the last decade, methods in imaging mass spectrometry (IMS) have progressively improved and diversified toward a variety of applications in natural products research. Because IMS allows for the spatial mapping of the production and distribution of biologically active molecules in situ, it facilitates phenotype and organelle driven discovery efforts. As practitioners of IMS for natural products discovery, we find one of the most important aspects of these experiments is the sample preparation and compatibility with different ionization sources that are available to a given researcher. As such, we have focused this mini review to cover types of ionization sources that have been used in natural products discovery applications and provided concrete examples of use for natural products discovery while discussing the advantages and limitations of each method. We aim for this article to serve as a resource to guide the broader natural product community interested in IMS toward the application/method that would best serve their natural product discovery needs given the sample and analyte(s) of interest. This mini review has been limited to applications using natural products and thus is not exhaustive of all possible ionization methods which have only been applied to image other types of samples such as mammalian tissues. Additionally, we briefly review how IMS has been coupled with other imaging platforms, such as microscopy, to enhance information outputs as well as offer our future perspectives on the incorporation of IMS in natural products discovery.