© 2014 Society for Adolescent Health and Medicine. All rights reserved. Purpose Although talking to youth about drugs is often recommended to parents, we know little about how parents actually discuss drugs with their children in the moment and how parental advice is linked to youth arousal and substance use. This study examined observed parental drug use advice and parenting behaviors during parent-adolescent drug use discussions and associations with adolescent physiological responses and substance use.Methods Fifty-eight 12-17 year olds and their primary caregivers participated in a laboratory session in which parents and youth discussed the topic of alcohol and/or drug use for 10 minutes. This discussion was videotaped and coded for drug use advice (rules against drug use, information on drug use consequences, scenarios or learning advice [discussing drug use scenarios and what the child has learned about drugs]) and general parenting behaviors (parental warmth and/or support, negative and/or critical parenting). Before, during, and after the discussions, adolescents' heart rate, blood pressure (BP), and salivary cortisol levels were assessed.Results Parental discussion of scenarios and/or learning was associated with lower adolescent BP responses to the discussions and lower likelihood of substance use. Parental discussion of rules against drug use was associated with higher heart rate and BP responses and greater likelihood of substance use. Criticism and/or negative parenting was associated with higher cortisol responses and greater likelihood of substance use at a trend level.Conclusions Parenting characterized by greater discussion of drug use scenarios and less stating of rules against drug use and criticism may make youth feel more comfortable and be linked to lower substance use.