There are multiple situations in the context of transfusion medicine where the classic serologic methods are unable to provide an adequate response, for example, recently polytransfused patients, patients with positive direct human antiglobulin tests, and hemolytic disease of the newborn. The traditional polymerase chain reaction techniques are slow and sometimes difficult to carry out and interpret. Thus there is a need for the development and validation of rapid and effective molecular methods. The genetic basis of the main alleles of the most important blood groups are known, but the frequencies vary in the different populations, thus for the genetic techniques to be efficient it is important to evaluate them, in order to adapt the molecular approaches.