The primary goal of red blood cell (RBC) transfusion is to improve the oxygen-carrying and delivery capacity of blood in patients with anemia. Though studies support a hemoglobin (Hb) threshold of 7 g/dL in hospitalized adult patients who are hemodynamically stable and 8 g/dL in patients undergoing orthopedic surgery, cardiac surgery, or with pre-existing cardiovascular disease, the clinical context of the individual patient must always be considered. To ensure safe administration of RBCs, pretransfusion testing must be performed in the blood bank to ensure immunologically compatible blood products are being provided. Selection of an RBC unit includes typing the patient’s RBCs for A, B, and D antigens and performing an antibody screen of the patient’s serum to identify alloantibodies to clinically significant RBC antigens. If alloantibodies are demonstrated, AB/Rh compatible RBC units lacking the corresponding antigens must be provided. This is followed by performing a crossmatch, in which immunologic compatibility between the patient and the allocated donor RBC unit is assessed. Finding crossmatch-compatible blood for individuals who are highly alloimmunized, such as multi-transfused patients with sickle cell disease (SCD), may be particularly challenging. Pre-storage leukoreduction of cellular blood products has almost universally been adopted in the USA to reduce alloimmunization to human leukocyte antigen (HLA) antigens, transmission of cytomegalovirus (CMV), cytokine-mediated febrile transfusion reactions, and platelet refractoriness, but washing or irradiation typically still need to be ordered on an as needed basis for severe allergic or transfusion-associated graft versus host disease, respectively. Red cells should not be withheld with life-threatening anemia, but one must always be vigilant to identify transfusion reactions. Any suspected reaction must be reported to the blood bank so that the necessary workup performed to ascertain to ascertain the nature of the reaction is performed.