The use of monoclonal antibodies has led to new therapeutic possibilities for many clinical conditions. However, their application also bears risks, as demonstrated by the acute occurrence of a cytokine storm following administration of TGN1412, an anti-CD28 superagonist, in March 2006. This article highlights the principles of the Paul-Ehrlich-Institut (PEI) for the scientific assessment of first-in-man clinical trial applications for monoclonal antibodies. These principles are implemented as a standard operating procedure in the PEI Quality Management System and are intended as a supplement specific to monoclonal antibodies to the published general guideline issued by the Committee for Medicinal Products for Human Use (CHMP). Central aspects are the identification of risk factors for monoclonal antibodies based on defined criteria, since not every novel monoclonal antibody represents a risk per se. Furthermore, a PEI expert group that supports the scientific assessment procedure has been founded.