Objective: Scientific advances in the field of addiction have forever debunked the notion that addiction reflects a character flaw under voluntary control, demonstrating instead that it is a bona fide disease of the brain. The aim of this review is to go beyond this consensus understanding and explore the most current evidence regarding the vast number of genetic, developmental, and environmental factors whose complex interactions modulate addiction risk and trajectory. Method: Focusing on childhood and adolescent smoking as a paradigm, we review the important risk factors for the development of addictions, starting at the level of genetics and closing with a focus on sociocultural and policy factors. Results: A critical review of the pertinent literature provides a detailed view of the cumulative power of risk and protection factors across different phenomenological levels to modulate the risk of undesirable outcomes, particularly for young people. The result represents a compelling argument for the need to engage in comprehensive, multilevel approaches to promoting health. Conclusions: Today, the field of medicine understands more about disease than about health; however it need not be that way. The view of drug addiction as a systems failure should help refocus our general approach to developing dynamic models and early comprehensive interventions that optimize the ways in which we prevent and treat a complex, developmental disorder such as drug addiction. (Contains 1 figure.)