<p>The digital twin concept promises to revolutionize all dimensions of the health sector, including healthcare planning and delivery, health promotion and education, and medical research. The present article maps the key legal and ethical challenges which will need to be addressed for a successful roll-out of digital twin models for children living with rare diseases, using the example of phenylketonuria (PKU) as model disease. The main legal challenges, which will arise in virtually all jurisdictions worldwide, have been analyzed with a focus on European Union law: data protection, medical device regulation, AI regulation, intellectual property, and product liability. The main ethical challenges have been analyzed using research and digital ethics frameworks of the WHO, UNESCO, HLEG-AI, and CIOMS: autonomy, informed consent to research, trust, and the impact on interpersonal relations, identity and self-understanding. Based on our analysis, we will identify shortcomings of current laws, regulations, and ethics guidelines. Clear legal and ethical guidance is, however, urgently needed to protect vulnerable groups of patients from harm, notably children living with rare diseases, and to help innovators navigate the complex legal and ethical issues the digital twin concept raises. Therefore, we call for an expansion of ongoing efforts to regulate artificial intelligence (e.g., at the EU and Council of Europe level) and of ethics guidance and training in the field (e.g., by the WHO and the UNESCO) to include guidance on the key challenges raised by digital twin models.</p>