Understanding the costs associated with blood products requires sophisticated knowledge about transfusion medicine and is attracting the attention of clinical and administrative healthcare sectors worldwide. To improve outcomes, blood usage must be optimized and expenditures controlled so that resources may be channeled toward other diagnostic, therapeutic, and technological initiatives. Estimating blood costs, however, is a complex undertaking, surpassing simple supply versus demand economics. Shrinking donor availability and application of a precautionary principle to minimize transfusion risks are factors that continue to drive the cost of blood products upward. Recognizing that historical accounting attempts to determine blood costs have varied in scope, perspective, and methodology, new approaches have been initiated to identify all potential cost elements related to blood and blood product administration. Activities are also under way to tie these elements together in a comprehensive and practical model that will be applicable to all single-donor blood products without regard to practice type (e.g., academic, private, multi- or single-center clinic). These initiatives, their rationale, importance, and future directions are described.