The objective of this systematic review was to identify and analyze the evidence base supporting the "30-minute" and "4-hour" rules in transfusion medicine. The 30-minute rule states that red blood cell (RBC) units left out of controlled temperature storage for more than 30 minutes should not be returned to storage for reissue; the 4-hour rule states that transfusion of RBC units should be completed within 4 hours of their removal from controlled temperature storage. Eligible studies were identified from searches (to October 2010) of a range of electronic databases (including The Cochrane Library, MEDLINE, EMBASE, and the National Health Service Blood and Transplant's Transfusion Evidence Library) and contact with transfusion medicine and blood bank experts. Twenty-three studies were identified that measured the quality of the RBC unit (n = 19), bacterial contamination in the RBC unit (n = 4), or both (n = 2) after exposure to greater than 4°C ± 2°C from between 20 minutes to 42 days. The overall finding was that temperature exposure did not adversely affect the quality of the RBC units or result in significant bacterial contamination. However, the variation in the temperature of exposure, its duration, the amount of data reported by the individual studies, and the age of the studies (and thus their comparability to current clinical practice) make it difficult to draw significant conclusions. To reliably determine whether these time "rules" could be extended without an adverse risk to the RBC unit requires robust, modern studies using multiple combinations of blood, anticoagulant, and additive solutions with defined temperatures and times of exposure. © 2012.