The blood group antigen Vel has been one of immunohematology's greatest enigmas: the variation in antigen strength from one individual to another, the property of anti-Vel to readily hemolyze Vel+ red blood cells (RBCs), and the difficulty to screen for sufficient numbers of Vel- blood donors had made Vel a tough nut to crack. In 2013, a small, previously unknown protein called small integral membrane protein 1 (SMIM1) was identified on the RBC by three independent research groups using different approaches, and all three groups demonstrated that Vel- RBCs lacked SMIM1. This discovery correlated with homozygosity for deletion c.64_60del in SMIM1 and meant that for the first time there was a universal method to screen for Vel- blood donors. This finding was not the whole answer, however, and an explanation behind the variability in antigen strength was later shown to be due to polymorphism in SMIM1 intron 2, a region that is responsible for gene transcription. Clinically, anti-Vel is important and has caused severe transfusion reactions, although hemolytic disease of the fetus and newborn caused by anti-Vel is uncommon. However, while screening for Vel- blood donors has become easier, the function of SMIM1 is still unknown, and despite its well-conserved sequence across the animal kingdom, the enigma continues.