Growing numbers of adolescents are marginalized by social factors beyond their control, leading to poor health outcomes for their families and future generations. Although the role of the social determinants of health has been recognized for many years, there is a gap in our knowledge about the strategies needed to address these factors in health promotion. Drawing on a review of literature on health promotion for marginalized and out-of-school adolescents, this paper highlights some urgent areas of focus for researchers and policy makers addressing adolescent health. Social determinants of health affecting marginalized adolescents identified by the review were education, gender, identity, homelessness, poverty, family structure, culture, religion and perceived racism, yet there is little solid evidence as to how to best address these factors. More systematic research, evaluation and global debate about long-term solutions to chronic poverty, lack of education and social marginalization are needed to break the cycle of ill health among vulnerable adolescents.