Human milk as well as the milk of several mammalian species contains, beside major nutrients and anti-infectious and immunocompetent substances, a group of biologically active substances called "milk-borne trophic factors" or "growth modulators". Milk-borne trophic can be classified into three groups: hormones and trophic peptides; nucleotides, nucleosides and derived substances; and polyamines, especially spermine and spermidine. Certain hormones and peptides such as growth hormone, insulin, insulin like-growth factor I (IGF-I), epidermal growth factor (EGF), prolactin and growth hormone releasing factor (GHRF) can influence directly newborn's metabolism after intestinal absorption and promote growth and differentiation of several organs and target tissues. They could exert a cytoprotective effect against toxins and toxic substances and reduce the potential risk of necrotizing enterocolitis. Nucleotides are present in human milk at high levels, and are precursors of nucleic acids, which implies that they can enhance growth and differentiation of several organs and tissues, especially the liver. Nucleotides from milk enhance lipid metabolism, lipoprotein synthesis and liver cell function and regeneration. In addition, they have a determinant action on the development of the gut associated lymphoid tissue (GALT). Lastly, polyamines, mainly spermine and spermidine, are polycationic substances virtually present in all cells, whose concentration in human milk is about ten times higher than in infant formulae. In addition, spermine and spermidine levels increase markedly during the first 3 days of lactation reaching, after 1 week, plateau levels which are respectively 12 and eight times higher than the levels measured at day 0. Although several experimental studies have shown that polyamines from the milk of lactating mammals determine important mitogenic, metabolic and immunological effects promoting growth and differentiation of the immature gastrointestinal tract of the offspring, their beneficial effects on growth and differentiation of the gastrointestinal tract in humans remain hypothetical. As a consequence, enrichment of milk formulae in one or in several trophic factors is an important but complex goal. Its practical realization is not realistic today because of a too great number of incertitudes. The most important is related to potential beneficial or adverse effects emerging at short or at long term and to the individual interactions of these substances which could be agonist and antagonist because they are naturally present in milk as a "complex cocktail" whose composition changes during the lactation period.