Several widely publicized errors in transplantation including a death due to ABO incompatibility, two HIV transmissions and two hepatitis C virus (HCV) transmissions have raised concerns about medical errors in organ transplantation. The root cause analysis of each of these events revealed preventable failures in the systems and processes of care as the underlying causes. In each event, no standardized system or redundant process was in place to mitigate the failures that led to the error. Additional system and process vulnerabilities such as poor clinician communication, erroneous data transcription and transmission were also identified. Organ transplantation, because it is highly complex, often stresses the systems and processes of care and, therefore, offers a unique opportunity to proactively identify vulnerabilities and potential failures. Initial steps have been taken to understand such issues through the OPTN/UNOS Operations and Safety Committee, the OPTN/UNOS Disease Transmission Advisory Committee (DTAC) and the current A2ALL ancillary Safety Study. However, to effectively improve patient safety in organ transplantation, the development of a process for reporting of preventable errors that affords protection and the support of empiric research is critical. Further, the transplant community needs to embrace the implementation of evidence-based system and process improvements that will mitigate existing safety vulnerabilities.