Estimates of the total overall costs of substance abuse in the United States, including productivity and healthand crimerelated costs exceed $600 billion annually (National Drug Intelligence Center 2011). This includes approximately $181 billion for illicit drugs, $193 billion for tobacco, and $235 billion for alcohol. In the USA, the root cause for 25 % of the total deaths can be attributed to substance abuse (Kochanek et al. 2011). The most commonly used drug among American youth is alcohol. Alcohol, the most commonly used drug among American teenagers, kills youth 6.5 times more often than other drugs of abuse (Rehm et al. 2009). And in the larger population, a death toll of nearly 10,000 can be attributed to chronic alcohol abuse within a timeframe of 1 year. Drug consumption of all types generally begins during adolescence; by 13 years of age, over 30 % of teens report having used at least one illicit substance (www.monitoringthefuture.org). As staggering as these numbers are, they do not fully describe the breadth of destructive public health and safety implications of substance abuse, such as family disintegration, loss of employment, failure in school, domestic violence, and child abuse, as well as the association of substance abuse with risky sex, HIV and other sexually transmitted diseases, heart disease, and cancer. In response to the gravity of this issue, hundreds of millions of research dollars have been spent on preventive intervention programs aimed at curbing high-risk behaviors, such as substance abuse. At the National Institutes of Health (NIH) alone, $1,674 million was spent in 2010 on substance abuse; more so than any other neurobehavioral disease. Despite this enormous amount of scholarly effort, however, most prevention research on substance abuse has neither focused upon, nor sought to ameliorate generative and oftentimes malleable mechanisms (e.g., neurocognitive deficits, stress reactivity) in substance abuse and related risk behaviors. In effect, although some recipients of prevention programming engage positively and achieve long-term success across multiple domains of functioning, many others respond less favorably, showing a trajectory toward onset and escalation of behavioral maladjustments, drug use initiation and escalation, lack of intervention engagement, and persistent intervention resistance. This problem has led to calls by many (National Research Council and Institute of Medicine 2009; Sloboda and Bukoski 2003) for a multiple-systems transdisciplinary approach that incorporates perspectives from fields such as genetics, neuroscience, developmental epidemiology, contextual behavioral science, environmental sciences, and clinical practice. Such an approach is crucial if we are to significantly advance scientific knowledge and the development of successful interventions in this area. Translation of findings on etiological underpinnings of substance abuse and related behaviors will lead to a better understanding of the significant impact of the social and physical environment on neurogenetic systems in ways that will inform development of personalized prevention approaches.