The ABO and Rhesus blood group systems are the most clinically relevant blood group systems from haemolytic disease of the foetus and newborn (HDFN) and haemolytic transfusion reaction (HTR) perspectives. Other clinically relevant blood group systems include the Kell, Duffy, Kidd and MNSs blood group systems. The clinical relevance of a blood group system depends on the ability of antibodies of the system to cause HDFN and HTR. This chapter discusses the distribution of ABO, Rhesus and other clinically relevant red cell antigens among Nigerians and implications for HDFN and HTR. There are several challenges associated with the management of Rhesus negative pregnancies, pregnancies associated with clinically significant alloantibodies, implementation of policy on routine antenatal anti-D prophylaxis (RAADP), management of Rhesus negative women that require termination of pregnancy (TOP), provision of antigen negative blood for certain patient groups and the management of pregnant and non-pregnant patients with clinically significant alloantibodies. This chapter highlights the need for Nigeria and other African countries to implement best practices to optimize the care offered to pregnant women as well as patients in whom red cell transfusion is indicated.