Hemolytic anemias caused by premature destruction of red blood cells occur in many disorders including hemoglobinopathies, autoimmune conditions, during infection or following reaction to drugs or transfusions. Recent studies which will be reviewed here have uncovered several novel mechanisms by which hemolysis can alter immunological functions and increase the risk of severe complications in hemolytic disorders. Plasma-free heme can induce the formation of neutrophil extracellular traps (NETs) through reactive oxygen species signaling. Although NETs protect the host against infections, in patients with sickle disease, they are associated with vaso-occlusive crises. Heme may increase host susceptibility to infections by inducing heme oxygenase 1 (HO-1) in immature neutrophils, thereby inhibiting oxidative burst required for clearance of engulfed bacteria. In addition, heme impairs macrophage phagocytosis and microbial clearance through inhibition of cytoskeletal remodeling. Hemolysis can also favor anti-inflammatory immune cell polarization by inhibiting dendritic cell maturation necessary for effector T-cell responses, inducing differentiation of monocytes into red pulp macrophages, important for iron recycling from senescent erythrocytes, and driving regulatory T-cell expansion through modulation of HO-1 expression in nonclassical monocytes. Hemolysis breakdown products show remarkable effects on the regulation of immune cell differentiation and function.