The determination of the structure of hemoglobin is one of the milestones of molecular biology. This information has provided an intimate understanding of the way in which the molecule functions physiologically; Study of hemoglobin has proved relevant to a number of biomedical disciplines. This protein is a prototype of a general class of allosteric enzymes whose function depends upon transition from one conformation to another. Recently, attention has been focused on environmental factors, including 2,3-DPG, hydrogen ion concentration, and CO2, which can modify and perhaps regulate the behavior of hemoglobin within the red cell. Comparisons of primary amino acid sequences of animal hemoglobins have provided new and independent phylogenetic insights. Furthermore, surveys of human hemoglobin phenotypes have been of considerable utility in the study of population genetics. Finally, certain variants are responsible for specific clinical syndromes. As we shall discuss in detail, in most cases the clinical features can be directly attributed to lesions at a submolecular level. This chapter will first present a detailed account of interrelationships between hemoglobin structure and function. Secondly, we will consider the various factors in health and disease which can modify hemoglobin's physiologic role. This background information will be useful in the consideration of inherited and acquired disorders of hemoglobin structure and function.