Mammary gland involution is a compound, physiological process that is characterized by de-differentiation and apoptosis of mammary epithelial cells. The involution is controlled by prolactin, growth hormones, estrogens, progesterone, cortisol and insulin-like growth factor 1 (IGF-1). Advanced pregnancy, infrequent milking, and mastitis increase the death of epithelial cells by apoptosis. Milk stasis triggers local stimuli, which cause the leak-tight junctions and initiate involution. Cows are especially susceptible to intramammary infections (IMI) by contagious pathogens at drying-off and environmental pathogens around parturition. High milk yield at dry-off is a significant risk factor for both cows and quarters infected with environmental pathogens at calving. Cows with high milk production rarely develop a keratin plug, which is the natural protection against infection during dry period. These cows require reduction in milk production at drying-off by restricted diet, interrupted milking or pharmacological treatment. From literature it is known that intramammary infusion of colchicine and endotoxin at drying off accelerates mammary involution. Infusion of ConA or PHA near drying off also accelerates bovine mammary involution, resulting in elevated levels of natural protective factors. Interleukin-2 accelerates involution and stimulates local antibody production more than did the pokeweed mitogen and LPS. Intramammary infusion of either rboGm-CSF or rboIl-1β at the cessation of milking immediately increases the number of phagocytic cells in the gland. These cytokines, particularly rboIl-1 β, can increase the rate of mammary gland involution. It is also stated that infusion of β1.3-glucan at drying-off accelerates the involution process through an increase in somatic cells, particularly in the numbers of macrophages in mammary secretions. Casein hydrolyzates are among the milk-borne factors that cause the disruption of tight junction integrity and induce involution in cows. Mammary tissue involution is effected by exogenous estrogen through the activation of plasminogen. Endogenous estrogen secreted by the developing fetal and placental unit might partially mediate the gradual involution that occurs during lactation.