The adaptive, humoral response to foreign antigens typically involves interactions between antigen-presenting cells, T cells and B cells resulting in alloantibody development. This is the classical model utilized by transfusion medicine physicians and scientists to explain alloimmunization to blood group antigens. Until recently, however, the intermediate processes by which antigen presentation induced T and B cell activation were poorly understood. Studies arising from basic immunology now suggest that components of the innate immune system, called pattern recognition receptors (PRRs), play an integral role in promoting T and B cell mediated responses. Innate PRR elements appear to "instruct" the adaptive, humoral arm of the immune system, thereby serving to initiate events that ultimately culminate in alloantibody formation. These exciting developments from the realm of basic immunology have many important implications for the field of transfusion medicine, and are particularly relevant to the induction of blood group alloantibodies following red cell exposure. Understanding the interaction between the innate and adaptive immune systems after transfusion may help to uncover the mechanisms underlying blood group alloimmunization. Moreover, such knowledge may allow transfusion medicine physicians and scientists to devise strategies to avoid provoking innate immunity and inducing an alloantibody response.