Homeostasis is the maintenance of equilibrium in a biological system by means of positive and negative feedback control mechanisms that counteract influences tending toward physiological dissonance. At the molecular level, homeostasis is controlled by the network of the neuro-endocrine-immune system, in which lactoferrin (LF) plays a central role. The purpose of this review is to provide a comprehensive summary of a collaborative study established between the Hirszfeld Institute of Immunology and Experimental Therapy (Wrocław, Poland) and the University of Texas Health Science Center (Houston, USA) regarding LF and its role in homeostasis. In our studies we focused on the immunoregulatory functions of LF, both in vitro and in vivo. We investigated the immune status of individuals subjected to different insults, including experimental endotoxemia in mice and surgery in humans. We also studied a LF-dependent delayed type hypersensitivity (DTH) response to evaluate some of the mechanisms by which LF can effectively substitute an adjuvant in vaccine.