Prior to 1900, blood transfusions were fraught with danger and often caused more complications than the underlying disease. Discovery of the ABO compatibility system in the early twentieth century opened the modern era of blood transfusion, yet ABO incompatibility-as a result of clerical error-remains a significant threat to the recipient today. The risk of disease transmission now includes new and emerging agents, such as Trepanosoma cruzii and West Nile Virus (WNV), as well as other existing pathogens. Transfusion-related immunomodulation (TRIM) presents a further risk to recipient patients. Confounding these problems are shortages of safe blood and the accelerated rise in the cost of blood due to increased testing. Outcome data on transfusion therapy have not always been favorable, particularly in the areas of postoperative infection, systemic inflammatory response syndrome (SIRS), multiple organ failure (MOF), and mortality. Such data have generated extensive efforts to determine association versus underlying cause of post-transfusion complications. In addition, unprecedented global initiatives to minimize the use of allogeneic blood are on the way. Options may include, but are not limited to, the use of "blood substitutes," although validation of such products is still required. In the meantime, blood product conservation techniques should become part of routine transfusion medicine.