Healthcare is undergoing a digital transformation through Artificial Intelligence (AI) systems, which collect and process vast amounts of personal health and genomic data. However, the processing of such data by AI systems and human–machine interactions can generate biases and place human beings in situations of vulnerability. The primary—and even more so, the secondary—use of these types of data by AI systems can, on the one hand, contribute to scientific research and lead to advances in disease prevention and treatment. On the other hand, it risks endangering the rule of law, with the uncertainty of distorted, opaque, or harmful decisions that could result in discrimination or violations of human rights. In recent years, the need for robust international regulatory support has become increasingly clear in Europe, aiming to successfully balance the protection of personal health and genomic data with their use by AI systems. The GDPR and the AI Act stand as strong expressions of this effort. By briefly referring to the French, German, and Spanish experiences—as the main countries compared with Italy—the aim is to identify the key legal frameworks concerning the secondary use of health and genomic personal data for scientific and clinical research purposes. Legal frameworks designed to safeguard individuals from new forms of vulnerability created by digital healthcare—or from pre-existing vulnerabilities exacerbated by the technologically advanced nature of society—must be profoundly connected to ethical principles. The European legislator’s primary objectives are to promote transparency in AI systems and to foster trust in their use. The more AI systems are built on principles of transparency, the better they can prevent risks related to unreliability and inspire public confidence.