In dairy cows, it is believed that the decrease in milk production after the peak of lactation is largely caused by mammary epithelial cell loss. However, the physiological regulations of lactation persistency in dairy ruminants are not entirely elucidated. Therefore, several experiments were conducted to assess the effects of hormonal and nutritional challenges on milk production and the mammary tissue. In a first experiment, the effect of the long-term inhibition of prolactin release was assessed at early lactation with cows receiving or not daily injections of quinagolide for 8 wk. The prolactin inhibition induced a faster decline in milk production (-14%) associated with a reduction in cell proliferation and an increase in apoptosis in the mammary tissue. Another experiment was conducted to observe the effects of sex steroids. Multiparous cows were either ovariectomized or sham-operated around 60 d in milk and followed for 52 weeks. Ovariectomy slowed the decline of milk yield (+10%) and thus, improved lactation persistency. This effect was accompanied with modifications of apoptosis/proliferation balance in the mammary tissue and a reduction of mammary epithelial exfoliation into milk. The effects of feeding level were also investigated in 2 experiments. In the first experiment, dairy cows were assigned to a basal diet or a severe feed restriction from 2 wk before calving to wk 11 postpartum. The negative effect of feed restriction on milk yield (-38%) was accompanied with a higher level of apoptosis in the mammary gland without effect on cell proliferation but affecting the total amount of DNA in the tissue. A second experiment, a moderate feed cows at early lactation for 4 weeks, decreased milk yield (-8%) without affecting the apoptosis/proliferation balance but increasing mammary epithelial cell exfoliation into milk. Altogether, these experiments confirmed that the regulation of lactation persistency in the dairy cows is related to changes in the number of mammary cells through either the regulation of apoptosis/proliferation balance but also through the rate of mammary cell exfoliation into milk.