This article examines the utility of a health and human rights framework for conceptualizing and responding to the causes and consequences of substance use among young people. It provides operational definitions of "youth" and "substances," a review of current international and national efforts to address substance use among youths, and an introduction to human rights and the intersection between health and human rights. A methodology for modeling vulnerability in relation to harmful substance use is introduced and contemporary international and national responses are discussed. When governments uphold their obligations to respect, protect, and fulfill human rights, vulnerability to harmful substance use and its consequences can be reduced.