This funding opportunity announcement (FOA) focuses on sensitivity and tolerance mechanisms underlying the development of alcohol use disorder. The intent of this FOA is to: (1) develop hypotheses about cellular, molecular or network mechanisms that regulate sensitivity and tolerance to alcohol, and (2) develop quantitative models to predict the development of tolerance and the progression to alcohol use disorder. These objectives will be accomplished with a Phased Innovation (R21/R33) mechanism, clinical trial optional, in which secondary data analysis or pilot studies can occur during the R21 phase, and research testing the hypotheses can be expanded in the R33 phase. The transition to the R33 phase will be determined by NIAAA program staff after evaluation of the achievement of specific milestones set for the R21 phase.