One approach to addressing observed health disparities that is frequently discussed in the literature is adapting health messages to the cultural identities of groups who experience an undue burden of disease. The extant research on the cultural tailoring and targeting (CTT) of health messages generally indicates that such adaptations are effective. However, the empirical basis for this conclusion does not provide definitive evidence that CTT is always necessary nor demonstrate that culturally adapted messages are always more effective than more general message appeals. Despite extensive literature on CTT, important questions remain about the necessary components, methodology, and evaluation of CTT research. In this essay, we present a set of criteria for assessing the existing research base for CTT and ensuring that future CTT research is valid, replicable, rigorous, and robust. Key considerations include identifying when CTT is necessary, conducting rigorous formative research, using appropriate experimental designs, designing message interventions in a way that enables generalization, and evaluating mediators in order to build explanatory theories of CTT.