The current challenge is how to determine the isolated effect of alcohol on the human brain. This question exists within all brain-based studies of addiction. As discussed in the Limitations, in human research it is virtually impossible to disentangle the influence of alcohol from the possible contaminator effects across myriad factors (e.g., maternal AU, family history of AUDs, genetic risk, social disadvantage, psychiatric comorbidity, co-occurring substance use). Importantly, this is as true in adolescent addiction neuroscience as it is within the field of adult addiction neuroscience. However, rather than representing an insurmountable limitation, we suggest that it is particularly important to continue to conduct this research with AU youth in order to empirically evaluate the impact of drinking on the developing brain. Polysubstance use is the norm for many AU youth, just like AU youth are more likely to come from families with positive alcohol histories (Feldstein & Miller, 2006). We believe that making every effort to limit these confounds, but also acknowledging that they exist in the ‘real world’ will yield the most generalizable results.