Hemoglobin (Hb) concentration is the outcome of the interaction between genetic variation and environmental factors, including nutritional status, sex, age, and altitude. Genetic diversity influencing this protein is complex and varies widely across populations. Variants related to abnormal Hb or altered characteristics of the erythrocytes increase the risk for anemia. The most prevalent are related to the inherited globin abnormalities affecting Hb production and structure. Malaria-endemic regions harbor the highest frequencies of variants associated with the most frequent monogenic diseases and the risk for nonnutritional anemia and are considered as public health problems. Variation in genes encoding for enzymes and membrane proteins in red blood cells also influence erythrocyte life span and risk for anemia. Most of these variants are rare. Interindividual variability of hematological parameters is also influenced by common genetic variation across the whole genome. Some of the identified variants are associated with Hb production, erythropoiesis, and iron metabolism. Specialized databases have been developed to organize and update the large body of available information on genetic variation related to Hb variation, their frequency, geographical distribution, and clinical significance. Our present review analyzed the underlying genetic factors that affect Hb concentrations, their clinical relevance, and geographical distribution across populations.