New prion-related disorders have emerged over the past 20 years, of which the most notable in the human context is variant Creutzfeldt-Jakob disease (CJD). This disorder is a challenge to medical and public health professionals seeking early detection and diagnosis, provision of therapy, and support for persons affected and a better understanding of transmission risks. The risk of iatrogenic transmission of the disease remains a significant threat, given the well documented cases of CJD transmission via surgery, organ transplantation, and blood transfusion. This review discusses our current understanding of the prevalence of variant CJD, the distribution of tissue infectivity, and new methods for the decontamination of surgical instruments. A comparison of emerging technologies is provided on the basis of our current perception of surgical risk to identify methods that are likely to provide sufficient safety margins and to stimulate debate about the standards needed to protect against variant CJD and CJD transmission.