C3d is the final degradation product of the third component of complement (C3). When conjugated to an antigen, C3d enhances immune responses to the fused antigen. Therefore, this molecule has been used as an adjuvant to enhance the immune responses to various foreign and self-proteins. C3d binds to the complement receptor 2 (CR2) that is located on the surface of follicular dendritic cells (FDC), B cells, and T cells in many species. C3d stimulates antigen presentation by FCD and helps to maintain immunological B cell memory. On B cells, C3d interaction with CR2 will collect molecules such as CD19, TAPA (CD81), and Lew 13. CD19 has a long intracellular tail that triggers a signaling cascade that results in cell activation and proliferation. Furthermore, simultaneous C3d-CR2 ligation and surface immunoglobulin (sIg) by antigen, activates two signaling pathways that cross-talk and synergize to activate B cells. However, C3d can enhance antibody titers in the absence of CR2 binding, indicating CR2-independent mechanism(s) of enhancement of the immune response. This review focuses on the complexity of the C3d-CR2 interaction, the importance of this interaction for the enhancement of the immune response by C3d and its derivatives, as well as the paradoxical enhancement of the immune response in the absence of CR2.