Human genome editing can be carried out on somatic cells as well as on the germline. In this paper I discuss first-in-human trials on both types of editing. At first sight, risk and risk/benefit assessment might seem to be key issues in such trials. However, according to decision theory, risk presupposes numerical values. In ‘decision-making under risk’, decisionmakers have sufficient information to assign probabilities to alternative outcomes. This is not the case in first-in-human trials. These trials are rather characterized by ‘decision-making under uncertainty’. My overall objective is to clarify the implications of uncertainty about benefit and uncertainty about harm in first-in-human trials on genome editing. A special aim is to analyse strategies for handling uncertainty.