Red blood cell (RBC) alloimmunization continues to challenge the foundational promise of transfusion therapy: to provide safe and universally effective support. Although most transfused individuals remain tolerant, a vulnerable minority develop alloantibodies that complicate care and increase the risk of delayed hemolytic transfusion reactions (DHTRs). While high-income nations increasingly mitigate this risk through molecular genotyping, low- and middle-income countries (LMICs) face a distinct landscape defined by antigenic mismatch and resource scarcity. This critical review evaluates alloimmunization not merely as a technical failure, but as a phenomenon driven by the collision of immunobiological susceptibility and structural health determinants. A structured literature review informed by PRISMA reporting recommendations was conducted to synthesize immunobiological and health-systems evidence across diverse epidemiological settings.We synthesize evidence on immune responsiveness alongside the economic realities of LMICs, where competing health priorities often necessitate trade-offs in laboratory capacity. By critically examining compatibility strategies through the lenses of feasibility and cost-effectiveness, we propose a risk-adapted, tiered framework for antigen matching. This approach challenges one-size-fits-all paradigms, suggesting that transfusion safety can be optimized by aligning biological risk with available resources rather than relying solely on inaccessible technologies.