The hemoglobin molecule can be studied with greater facility than any other human protein. This is because blood can easily be taken from many individuals, hemoglobin is the principal protein of red blood cells, and its extraction does not require complicated biochemical methods. It is therefore not surprising that this protein is the most thoroughly studied and the globin genes the best analyzed in humans. Work on human hemoglobin began with the investigation of sickle cell disease (SCD) in 1910, and in 1925 Cooley and Lee first described a form of severe anemia associated with splenomegaly amd characteristic bone changes. This condition has been known since then as thalassemia - a term derived from the Greek word θαλασσα (thalassa =sea), referring to the Mediterranean Sea - or Cooley's anemia. Genetically oriented studies of human hemoglobins have proceeded apace, starting with the elucidation of the amino acid sequence and structure of the molecule in the 1960s. The hemoglobin system is currently a paradigm for the understanding of gene action at the molecular level. Hemoglobin research is comparable in human biochemical and molecular genetics to that of research on Drosophila and phage in basic genetics. Most concepts derived from hemoglobin research can be readily applied to other proteins, and it has been possible to teach many conceptual principles of human genetics by means of examples from the hemoglobin system. This chapter summarizes the main aspects of human hemoglobin research that has provided, overall, important insights into: (a) Protein structure and function, (b) Gene structure and expression, (c) Developmental gene regulation, (d) Long-range gene interactions and chromatin structure, (e) Gene evolution, (f) Genotype-phenotype relationships and phenotype modifiers, (g) Mechanisms of action of pathogenic mutations, (h) Polymorphisms and haplotype blocks, (i) Molecular diagnostics of inherited disorders, and (j) Gene therapy of monogenic disorders.