At the meeting of the ISBT working party for red cell immunogenetics and blood group nomenclature in 2012, FORS, JR and LAN were ratified as blood group systems. Since then, the molecular basis of the Vel blood group antigen has been elucidated, and the complement regulator protein, CD59 has been shown itself to be a blood group antigen. These last two discoveries will no doubt lead to their elevation to blood group systems. How has this happened? It turns out to be a mixture of old and new techniques. Rapid advances in molecular biology and in our understanding of the human genome have opened new fields of discovery within human blood groups. The development of comprehensive SNP arrays, exome sequencing and rapid sequencing techniques, e.g. Next-Generation sequencing, has provide us with tools for rapid discovery. Combining these with sophisticated algorithms for database mining has resulted in the identification of the molecular bases behind the hitherto unresolved, clinically relevant blood group antigens Jra (ABCG2) and Vel (SMIM1). However classic biochemistry and subsequent peptide and DNA-sequencing still play an important role and lie behind the (simultaneous) discoveries of Jra and Vel, but also of Lan (ABCB6) and FORS (GBGT1). A rare CD59-deficient patient produced an alloantibody to a high-prevalence antigen that was shown to be targeted at CD59.