Over the past decades, clinical research has increasingly been subjected to ethical requirements and legal regulation. The specific focus of ethical and legal frameworks on competent adults (which serve as the paradigmatic research subject), however, has created an ambivalent attitude towards pediatric clinical research. On one hand, minors are regarded as a vulnerable population that deserves additional protection against the risks and burdens involved in clinical research. On the other hand, the population of minors should not be denied (or not get timely) access to the benefits of clinical research. In this paper, we will explore the legal regulation and ethical guidance that currently governs pediatric clinical research in the European Union and discuss the future challenges in this field. In addition, we will discuss major ethical concerns in pediatric clinical research, with a focus on the acceptability of research risks and the informed consent process. In the discussion, we will address key concerns in both regulating pediatric clinical research and implementing ethical and legal requirement in the actual pediatric research conduct.