At the end of their report on the successful selective breeding of rat strains with either high or low susceptibilities to morphine addiction, Nichols and Hsiao (1967) conjecture that, although ‘‘we have not yet isolated the factors responsible for the difference in addiction liability, one factor seems to be passed on from generation to generation.’’ That quaintly optimistic notion of ‘‘one factor’’ notwithstanding, this seminal study offers one of the earliest pieces of experimental evidence for the hereditary nature of addiction. Forty years later, and thanks to the findings from epidemiology and genetics studies, the general concept that addiction ‘‘runs in families’’ is beyond dispute, but teasing apart the timing, strength and contingent nature of the genetic contribution to addiction remains the focus of challenging research. It is typically difficult to establish causal relationships between genetic/genomic variation and the risk of suffering from complex diseases. The factors that contribute to this are many: multiple common gene variants with small effects, non-linear interactions between genetic variants (epistasis) and phenotype severity, complex networks of gene–gene interactions, and similar phenotypes arising from distinct gene variants, just to name a few. In the case of substance use disorders (SUD), the powerful modulatory role played by complex environmental factors on brain processes, which further muddle the picture, is particularly relevant. This is because, in the absence of drug exposure, itself an environmental factor, the specific addiction phenotype would remain hidden, even in the presence of an overwhelming genetic load. On the other hand, brain development and architecture, which are partly determined by genetic factors, can be affected by exposure to drugs. These two-way interactions highlight the importance of genes involved in human brain development and function in the subsequent emergence of personality styles and of emotional and behavioral reactivities. Indeed, multidisciplinary evidence reveals that the deceivingly simple concept of ‘‘genetics of addiction’’ belies the existence of a dense array of different interwoven layers whereupon genes, developmental processes, and environmental factors interact to increase or decrease the risk for SUD (Fig. 1a). In this special issue we have attempted to bring together different yet complementary research strategies whose ultimate goal is to better understand how genes contribute to SUD, including their effects on the various layers that determine whether and how the disease of addiction will be manifested (Fig. 1b). In this introduction we use the term addiction rather than the term ‘‘dependence’’ as described in DSM IV to avoid confusion with physical dependence, which is neurobiologically and clinically distinct from addiction. We refer to addiction as the phenotype characterized by the compulsive administration of the drug and the loss of control over its intake despite its adverse consequences to the individual. Note that, while relevant, we have not included a paper on the role of genes in brain development; readers interested in this topic are referred to various published reviews in the literature (Toga and Thompson 2005; Hariri 2009; Jedema et al. 2010; Mochida and Walsh 2004). N. D. Volkow (&) National Institute on Drug Abuse, National Human Research Institute, National Institutes of Health, U.S. Department of Health and Human Services, Rockville, MD 20892-9581, USA e-mail: nvolkow@nida.nih.gov