One of the four major goals outlined in the National Institute of Mental Health (NIMH) strategic plan (2021) is to develop and test new treatments and prevention strategies. The aim of the Funding Opportunity Announcement (FOA) for the R61/R33 grant mechanism has been to support the efficient pilot testing of exploratory clinical trials of novel interventions for mental disorders in adults and children through an experimental therapeutics approach. The present commentary (a) describes the R61/R33 grant mechanism, defines terms, and summarizes information about current grants in the system, (b) outlines the review criteria, and (c) highlights several common critiques. Frequent concerns expressed by applicants as well as reviewers include defining and measuring the target/mechanism, establishing dose, selecting an appropriate control group, measuring fidelity, and determining power. Finally, alternative pathways for conducting randomized clinical trials for intervention development are discussed in contrast to or in addition to the experimental therapeutics approach for discovering novel interventions aimed at reducing and preventing mental illness across the lifespan.