Production of blood components for transfusion requires that users have confidence in the quality of the products and that they will be safe and efficacious. The assurance of blood product quality requires the collection of data that demonstrate products are within specification. However, the linkage between confidence that an individual blood component unit will perform as expected and the conduct of quality testing is imperfect because quality testing is often done after product release and monitors process control, not quality control. In addition, the standards to assess blood components often allow a percentage of units to fail to meet user specifications. Ideally, there would be real time quality control measures made prior to unit release to the hospital blood bank, and these measures would be highly predictive of product efficacy. As a community, much work must be done to reach this state. First we must identify product characteristics that are strongly predictive of transfusion efficacy to use as standards. Improved production methods are only one way to impact component quality; another is to manage the characteristics of the donors themselves. Donor variation includes not only recognized wide ranges of traditional characteristics of normal healthy humans, but also extends to storage characteristics of components made from individual donations. This review covers the state of the science of product quality and the regulation of blood products, including new information arising from clinical studies and the application of modern scientific methods such as proteomics and metabolomics to blood component quality.