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Background: Although a low health literacy level has been found to be among the most powerful predictors of poor health outcomes, there is very little research focused on assessing and improving the health literacy skills of adolescents, particularly those from socioeconomically disadvantaged backgrounds. The vast majority of existing research focuses solely on reading comprehension, despite the fact that health literacy is actually a multifaceted concept, which entails many different types of skills., Objective: The aim of this paper is to first mine existing literature to identify the many different skills that have been posited to constitute health literacy, and then, using this collection of skills as an overarching structure, to highlight the challenges that disadvantaged youth participating in our HackHealth after-school program encounter as they identify and articulate their health-related information needs, search for health-related information online, assess the relevance and credibility of this information, and manage and make use of it., Methods: We utilized the design-based research method to design, implement, and revise our HackHealth program. To collect data regarding HackHealth participants' health literacy skills and associated challenges, we used a variety of methods, including participant observation, surveys, interviews, focus groups, and logging of Web browser activities. We also collected data through specialized instructional activities and data collection forms that we developed for this purpose. Quantitative and qualitative techniques were used to analyze this data, as well as all of the artifacts that each student produced, including their final projects., Results: We identified the various challenges that the 30 HackHealth participants faced in completing various health-related information activities during the course of the program. Based on these findings, we describe important implications for working with youth from socioeconomically disadvantaged backgrounds, how to assess and improve their health literacy skills, and offer specific recommendations for health literacy instruction aimed at this population., Conclusions: With an increased societal focus on health and a shift from viewing patients as passive recipients of medical care to viewing them as active arbiters of their own health, today's youth need to possess an array of health literacy skills to ensure that they can live long and healthy lives. Working with adolescents to help them develop and practice these skills will also help to break the cycle between poor health literacy and poor health outcomes, thereby reducing health disparities and improving the long-term outlook for the health of our nation.