The process of DNA fingerprinting was developed by Alec Jeffreys in 1984, and it first became available for paternity testing in 1988. Before this sort of DNA analysis was available, blood types were the most common factor considered in human paternity testing. Blood groups are a popular example of Mendelian genetics at work. After all, there are numerous human blood groups with multiple alleles, and these alleles exhibit a range of dominance patterns.

Today, the best-known blood-typing system is ABO typing, which involves the presence of antigens on red blood cells that are encoded by the ABO locus on human chromosome 9. In the ABO system, the A allele and the B allele are codominant, and the O allele is recessive. Thus, if a person's ABO blood type is O, he or she has two O alleles. If, however, a person's blood type is A, he or she has either two A alleles or one A allele and one O allele. Similarly, if a person has type B blood, this indicates the presence of either two B alleles or one B allele and one O allele. Finally, some people have type AB blood, which means they inherited both an A allele and a B allele.

In cases of questioned paternity, ABO blood-typing can be used to exclude a man from being a child's father. For example, a man who has type AB blood could not father a child with type O blood, because he would pass on either the A or the B allele to all of his offspring. Despite their usefulness in this regard, ABO blood groups cannot be used to confirm whether a man is indeed a child's father. Because of this and several other factors, it took the legal system some time to trust blood-typing. For example, in a famous case in 1943, the starlet Joan Barry accused actor Charlie Chaplin of fathering her child. Although blood tests definitively excluded Chaplin as the father, the court did not allow this evidence to be admitted, and Chaplin was ordered to pay child support to Barry. The Barry/Chaplin case did spur the passage of new laws, however, thus launching a new era in forensic evidence.

Over time, the use of additional blood antigens, such as those associated with the MN and Rh systems, refined the use of blood-typing for both paternity and forensics. However, such blood groups were only about 40% effective in ruling out a man as a child's father. Then, in the 1970s, testing for human leukocyte antigens (HLAs) added a distinguishing feature that made it possible to rule out men as fathers with 80% effectiveness. The genes responsible for the HLA system are involved in antigen presentation to T cells. The HLA system is highly polymorphic, with more than 3,200 different alleles identified so far (Robinson et al., 2003; Williams, 2001). Although this vast number of alleles causes headaches for cell and organ transplants, the multiplicity of genotypes the HLA system provides—in the tens of millions—makes it ideal for consideration in identity and paternity testing.