For public health protection, informed decision-making relies on having a robust foundation of evidence concerning risks and their prevention. Application of an evidence-based framework depends on the availability of pertinent, scientifically sound data generated by well-directed and valid research endeavors. In this essay, we address the current state of research in humans and the evidential base concerning high-concentration delta-9-tetrahydrocannabinol (delta-9-THC) products, which are readily available in the United States. Furthermore, we explore the intricate challenges faced in carrying out research on these products, which reflect the full range of study design issues: measurement of exposure and outcomes, confounding, selection bias, and the generalizability of findings. We offer recommendations to guide future research toward providing more informative evidence. By following these recommendations, researchers and funders on this emerging topic could move toward generating the valid and comprehensive evidence needed to effectively inform public health initiatives and guide policy decisions regarding high-concentration delta-9-THC products and their use. The urgency of generating such evidence cannot be overstated, given the widespread legalization and increasing availability and use of these products. (Am J Public Health. 2024;114(S8):S639-S644. https://doi.org/10.2105/AJPH.2024.307724).