System of innate immunity is a set of effector molecules and cells counteracting invasion of pathogens and their products. Alpha-2-macroglobulin (a2-MG) and lactoferrin (LF) play a significant role in primary protection of organism. A wide spectrum of transport and regulatory functions, high affinity to endocytosis receptor as well as structural features of these proteins allow them not only to effectively protect the organism during direct contact with pathogen but also to have an immunomodulatory impact on immunocompetent cells of adaptive immunity. However despite a common receptor and a number of ligands, mechanisms of realization of protective functions ofa2-MG and LF differ significantly. The aim of this review is to systemize knowledge on means and mechanisms of protection of a 2-MG and LF against invasion.