Abstract Health literacy is pivotal for advancing public health, empowering individuals to grasp health information and make informed decisions. However, health literacy levels are often influenced by social and economic factors, with lower levels correlating with reduced disease-specific knowledge and underutilization of preventive health services. As healthcare technology rapidly evolves, particularly with the advent of personalised medicine (PM) and novel genetic testing methods, there’s an increasing demand for heightened health literacy to effectively navigate these transformative innovations and optimize health outcomes. The European ExACT project aims to assess the understanding of PM and related technologies across the EU. In this context, through a survey conducted in several European countries, including Italy, France, Spain, Poland, the Netherlands, Romania, Hungary, and Germany, demographic data and attitudes towards PM, genetic testing, health portals, and big data were gathered. Logistic regression analysis identified factors influencing knowledge and attitudes. Among 6581 respondents, the results highlight a broad awareness of genetic testing (81%) and health portals (54%) yet a lesser familiarity with PM (48%) and big data (37%). Education level, age, and gender influenced awareness, with Hungary showing significant awareness across all topics (OR 2.09 95%CI 1.46-2.98), Spain excelling in big data (OR 1.88 95%CI 1.55-2.27), and Poland leading in genetic testing knowledge (OR 2.68 95%CI 1.82-3.96). Differences between countries may indicate successful policies and factors that can be replicated. Overall, the study emphasizes the importance of enhancing health literacy and sheds light on the predicting role of sociodemographic factors. It underscores the significance of bolstering health literacy to effectively navigate the advancements in PM and digital health, improving health outcomes in light of these evolving healthcare landscapes. Key messages • In Europe, awareness of personalised medicine, health portals and big data is lacking. Educational initiatives are crucial for effective navigation of innovations, considering regional differences. • Social and economic factors affect health literacy levels, impacting disease-specific knowledge and healthcare utilization.