||Remodeling of the mammary gland is dependent upon apoptosis and factors contributing to regression. In mice, irreversible involution is characterized by declining expression of milk proteins, increasing apoptosis, and a shift in the general architecture of the gland from the structures of lactation to a regressive morphology dominated by adipocytes. Within 24 hr of weaning, protein levels of whey acidic protein (WAP) and β-casein are plummeting. Cathepsin L mRNA is upregulated at 24 hr and proteins peak 36 hr after forced weaning. Interference with cathepsin L proteolytic activity and resultant lactation suggest that milk protein genes are likely targets of cathepsin L. Cathepsin L is responsive to Z-FY-CHO, a synthetic inhibitor. The blockade of cathepsin L by Z-FY-CHO is associated with extended milk protein expression up to 120 hr. This investigational model provides evidence that cathepsin L plays a regulatory role in milk protein gene expression and cathepsin L inhibited delays involution.