ABSTRACT Introduction Substance use disorders are extremely costly to the individual and to society, and a substantial proportion of patients do not respond to the therapies offered. To improve existing treatments a better understanding of the neurobiological and genetic basis of addictive behaviour and substance use disorder is warranted. The aim of this lecture is to develop a model of integrated translational addiction research which may result in the establishment of individualized therapeutic approaches for patients with substance use disorders. Methods The genetic basis of substance use disorders is characterized by a contribution of multiple genes to the clinical phenotype. This genetic complexity is based on poly/oligogenicity and genetic heterogeneity, two parallel mechanisms which are present to varying extents in different substance use disorders. To disentangle the complexity and to identify the genetic and neurobiological basis of addictions an integrated, translational approach involving (functional) genetic analyses, animal behavioural experimentation and neuroimaging studies is proposed. Results Examples of this approach are provided by describing a line of work which identified the relevance of circadian rhythm genes in regulating alcohol drinking behaviour in animal models and humans, as well as a complementary approach using endophenotypes in human gene-neuroimaging studies where the effect of single and combined genetic variations on processing of aversive emotional stimuli in the limbic system was demonstrated. Discussion While the combination of genetic, behavioural and neuroimaging analyses are shown to be useful tools to address oligogenicity and genetic heterogeneity in substance use disorders, the clinical relevance of this approach needs to be developed further. Thus, two current major research projects, the European integrated project ‘IMAGEN’ and the NIHR-Biomedical Research Centre ‘Mental Health’ in the United Kingdom, which potentially integrate our proposed research strategy with clinically relevant outcomes, will be discussed.