Red blood cell (RBC) alloantibodies develop in a subset of individuals following exposure to non‐self RBCs through transfusion, pregnancy or other activities; these antibodies can lead to difficulty locating compatible RBCs, acute or delayed haemolytic transfusion reactions, or haemolytic disease of the newborn. Alloimmunization is underestimated due in part to antibody evanescence, the random nature of post‐transfusion antibody screens, fragmented medical care and the lack of widespread antibody registries. Factors that influence who will develop detectable alloantibodies are not well understood. Transfusion burden is one risk factor for alloimmunization, though many highly transfused individuals never form alloantibodies despite exposure to many RBC units (and many non‐self blood group antigens). Individuals with sickle‐cell disease (SCD) and myelodysplastic syndrome (MDS) are more likely to form RBC alloantibodies than most other patient populations. Individuals with rheumatologic and other forms of autoimmunity, though not chronically transfused, are also at higher‐than‐average risk of forming RBC alloantibodies. Inflammation, in a broad sense, is one common thread amongst these diagnoses associated with high prevalence rates of RBC alloimmunization. Reductionist murine models support some types of inflammation (including viral‐like stimuli) around the time of RBC exposure as being associated with an increased likelihood of alloantibody formation. Strategies other than transfusion avoidance or extended antigen matching beyond ABO/Rh would be beneficial to prevent new RBC alloantibody formation, especially in patients at highest risk.