The sudden appearance and spread of Internet addiction in adolescent populations, in association with the rapid escalation of consumed Internet content and the broad availability of smartphones and tablets with Internet access, is posing a new challenge for classical addictology which requires urgent solutions. Like the majority of other psychopathological conditions, pathological Internet addiction depends upon a group of multifactor polygenic conditions. For each specific case, there is a unique combination of inherited characteristics (nervous tissue structure, secretion, degradation, and reception of neuromediators), and many are extra-environment factors (family-related, social, and ethnic-cultural). One of the main challenges in the development of the bio-psychosocial model of Internet addiction is to determine which genes and neuromediators are responsible for increased addiction susceptibility. This information will herald the start of a search for new therapeutic targets and the development of early prevention strategies, including the assessment of genetic risk levels. This review summarizes the literature and currently available knowledge related to neurobiological risk factors regarding Internet addiction in adolescents. Genetic, neurochemical and neuroimaging data are presented with links to actual pathogenetic hypotheses according to the bio-psychosocial model of IA forming.