The English & Romanian Adoptees (ERA) study follows children who spent their first years of life in extremely depriving Romanian institutions before they were adopted by families in the UK. The ERA study constitutes a “natural experiment” that allows the examination of the effects of radical environmental change from a profoundly depriving institutional environment to an adoptive family home. The cohort has been assessed at ages 4, 6, 11, and 15 years, and has provided seminal insights into the effects of early global deprivation. The current paper focuses on the long-term psychological sequelae associated with deprivation experiences. These deprivation-specific problems (DSPs) constitute a striking pattern of behavioral impairments, in its core characterized by deficits in social cognition and behavior, as well as quasi-autistic features, often accompanied by cognitive impairment and symptoms of attention-deficit/hyperactivity disorder (ADHD). Possible moderating influences, including variations in family environment, pre-adoption characteristics, and genetic variation, will be discussed to answer the question why some individuals have prospered while others have struggled. Apart from findings on the moderating effect of variation in genes associated with serotonergic and dopaminergic signaling involving specific phenotypes, heterogeneity in outcome is largely unexplained. The review concludes with an outlook on currently ongoing and future research of the ERA study cohort, which involves the investigation of neurobiological and epigenetic mechanisms as possible mediators of the long-term effects of institutional deprivation.