Whole blood/packed red blood cells (pRBC) units transfused in the U.S. totaled 13,785,000 in 2011. A single institution in South Dakota transfused 6,485 units of pRBC in 2013. Current thresholds for transfusion have changed and each transfusion has the risk of causing an adverse reaction; thus, it is important to ensure pRBCs are administered appropriately. Due to these changes and the potential risks associated with transfusion, we reviewed the literature regarding appropriate indications for transfusion of pRBC. Our review specifically focused on four disease entities: iron-deficiency anemia, acute upper gastrointestinal (GI) bleeding, acute coronary syndromes, and chronic ischemic heart disease. Based on our findings, we recommend utilizing an overall conservative approach to the transfusion of pRBC. In patients with iron-deficiency anemia, first try alternative methods to improve hemoglobin levels; in those with acute GI bleeding, transfuse for hemoglobin less than 7 g/dL; in patients with acute coronary syndromes, let symptoms/signs be your guide; and in patients with ischemic heart disease, transfuse for hemoglobin levels less than 8 g/dL or if they are symptomatic. Most importantly, be cautious to not fixate on numbers alone; always incorporate patients' symptoms and co-morbidities when considering whether to transfuse pRBCs.