Background Adolescent depression and anxiety are highly prevalent, recurrent, and disabling mental health conditions. Current treatment outcomes are suboptimal, often leaving young people with residual symptoms and high relapse rates. To inform future development of more effective preventative strategies, the Emotional Vulnerability in Adolescents (EVA) study aimed to identify vulnerability markers for adolescent depression and anxiety. Specifically, it examined the associations between mental health outcomes and potentially modifiable biopsychosocial factors. The present report provides an overview of the study design and methodology, summarised the demographic, clinical, and mechanistic characteristics of the sample, and examined individual differences by age, gender, and personal and familial history of mental health at baseline. Methods Data collection was conducted across three-time points (baseline, 6-months and a 60-month follow-up). A total of 425 adolescents (60.5% female) aged 12 -18 years (Mean = 15.06, SD = 1.75) were recruited at baseline. . A comprehensive battery of measures to assess a range of bio-psycho-social factors was employed. Results We replicated previous findings in suggesting that females and those with a personal or familial history of mental health difficulties have higher levels of depression and anxiety and lower levels of well-being. These vulnerable sub-groups were also found to differ from their counterparts in a number of biopsychosocial factors; specifically they showed poorer sleep quality, lower levels of resilience, and higher levels of rumination, stress, neuroticism, external shame, bullying experiences, neural-cognitive biases, and dysfunctional attitudes. Furthermore, symptoms of depression and anxiety increased with age and peaked around age 15; age was also associated with an increased risk for eating disorders. Conclusions The present findings highlight the importance of considering individual differences in developing future preventative and intervention strategies by targeting underlying mechanisms that are more specifically prominent in each individual subgroup of the population.