Every day physicians are confronted with situations that require evaluation concerning the indication for a post-exposition prophylaxis (PEP) for HIV or, less frequently, for hepatitis B (HBV). There is no specific prophylaxis for hepatitis C (HCV). In light of the experience gained in the domain of HIV in the last years, some international guidelines for PEP have been changed with regard to the choice of drugs and when to start PEP. This article attempts to resume the different factors contributing to the evaluation of PEP according to the local guidelines and to introduce the foreseen changes in the new Swiss-guidelines for PEP that will be released in autumn 2013.