Chloroquine diphosphate (CDP) is a helpful tool in the blood bank for two main applications. The most common application is to render direct antiglobulin test-positive red blood cells (RBCs) free from membrane-bound IgG; these treated RBCs can then be used for autologous adsorption and/or to determine the patient's RBC phenotype. Another common use of CDP is to remove human leukocyte antigens (HLAs) from RBCs to help identify or exclude the presence of antibodies to HLAs expressed on RBCs, for example, Bennett-Goodspeed (Bg) antigens. In this review, the principles, applications, and limitations of using CDP are discussed. Immunohematology 2018;34:98-102.