Children participating in clinical research may show signs of discomfort, discontent, dissent and so on, that cannot be solved by comforting the child. When, and on what ground, should such signs lead to the decision to withdraw the child from the trial? In order to adequately protect children participating in clinical research, it is important to know how to determine during the course of a trial whether participation is still justified. Yet to date, legislation, ethical guidelines and medical ethical literature do not provide sufficient guidance. Therefore, in this paper we aim to provide the required clarity. We identify two types of reasons for taking signs of discomfort, discontent, dissent and so on, very seriously: (1) the principle of respect for the growing autonomy of the child, in those cases where a child expresses a clear, explicit and persistent wish to be withdrawn from the study; and (2) the principle of non-maleficence, in those cases where for an individual child, the research burden appears to be higher than acceptable. We recommend to closely monitor each child during the course of the study, thereby being vigilant to whether the child still wants to continue and to whether the actual burden the child experiences is still acceptable in relation to the permitted levels of burden.