Lactoferrin (Lf) is an essential element of innate immunity, which refers to antigen-nonspecific defense mechanisms that a host uses immediately or within hours after exposure to an antigen. Following infection, Lf is released from neutrophils (PMNs) in blood and inflamed tissues and, such as other soluble pattern-recognition receptors of the innate immunity, Lf recognizes unique microbial molecules called pathogen-associated molecular patterns (PAMPs): LPS from the gram-negative cell wall and bacterial unmethylated CpG DNA. However, unlike classical PAMPs receptors involved in the activation of immune cells, Lf may act either as a competitor for these receptors or as a partner molecule, depending on the physiological status of the organism. These immunomodulatory properties are explained by the ability of Lf to interact with proteoglycans and receptors on the surface of mammalian cells: cells of the innate (NK cells, neutrophils, macrophages, basophils, neutrophils and mast cells) and adaptive [lymphocytes and antigen-presenting cells (APCs)] immune systems, and also epithelial and endothelial cells. Through these interactions, Lf is able to modulate the migration, maturation and functions of immune cells, and thus to influence both adaptive and innate immunities. The understanding of the roles of the host-expressed Lf in immunity comes from in vivo and in vitro studies with exogenous Lf which, although informative, rarely reflect the pathological, or non-pathological, conditions in the organism. In this review, the data from the literature will be critically analyzed in order to present a real picture of the regulatory roles of host Lf in immunity.