The implementation of a program on routine antenatal anti-D prophylaxis (RAADP) in the developed world has led to a significant decline in the residual numbers of Rhesus negative women becoming sensitized. However, a significant number of Rhesus D negative women in SSA are not fortunate because of lack of access to prophylactic immunoglobulin D and thus they continue to be affected. The management of Rhesus negative pregnancy in Sub-Saharan Africa is associated with several daunting challenges: absence of a policy on universal access to Rh D immunoglobulin, lack of fetomaternal testing facilities, unaffordability of prophylactic anti-D immunoglobulin, poor uptake of quality antenatal care, poor health infrastructure, sub optimal management of potentially sensitizing events during pregnancy, shortage of qualified medical personnel, poor data management, high incidence of illegal abortion and quackery. There is a need for the formulation of necessary guidelines on Rhesus immunoprophylaxis in SSA. Health authorities need to implement evidence-based policy on universal access to anti-D immunoglobulin. There is also the need to optimize the knowledge of obstetricians on anti-D prophylaxis, implementation of the readily available and affordable Kleihauer fetomaternal haemorrhage testing for all women who experience a potentially sensitizing event antenatally post 20 weeks gestation and postnatally. These factors can facilitate the effective management of Rh negative pregnancy in the region and reduce the risk of Rhesus D immunization and Rhesus D haemolytic disease of the foetus and newborn.