The first example of anti-Di^a was discovered in Venezuela in 1956, as a cause of hemolytic disease of the newborn. The family was Caucasian but there appeared to be Native American admixture. This led to the recognition that Di^a was a useful marker for persons of Mongolian descent while being of very low frequency in other populations. The frequency in Native Americans ranges from 2-36% while 3-10% of Orientals are positive. Anti-Di^b was not recognized until 1967 when two examples were reported in two Mexican women that were being transfused.

The Diego system remained a two antigen system until the 1990s when Di^a, Di^b and the Wright antigens (Wr^a and Wr^b) were determined to be amino acid substitutions on band 3, the anion exchange protein (AE1). The system quickly expanded when other antigens of low frequency were also identified on band 3 including: ELO, Redelberger, Traversu, Warrior, Wulfsberg, VanVugt, Waldner, Bishop, Hughes and Moen. No red cell lacking band 3 has been reported for this system which may indicate that its loss is lethal. There has been only one report of the Di(a-b-) phenotype. Antibodies to Wr^a are frequently found in patients having autoimmune hemolytic anemia or individuals having a positive direct antiglobulin test.