Understanding the cascade of gene expression and subsequent protein interactions that result both in the death of secretory mammary epithelium and the remodeling and renewal of the mammary gland for another cycle of lactation poses significant challenges (see Chapters 7 and 8, this volume). The complexity of mammary gland involution warrants caution in sorting through the various potential regulators and executors of apoptotic cell death in the mammary gland. As demonstrated by the number of remodeling enzymes expressed during involution, the relationship between mammary epithelium and its related mesenchyme is important for maintenance of differentiated function (Barcellos-Hoff et al., 1989; Streuli et al., 1991). Components of the extracellular matrix may play the role of survival factors, or may provide a source of factors, as a reserve of matrix-bound growth factors, necessary for survival of the secretory epithelium. Perturbation of this interaction alters mammary-specific differentiation gene expression, for example, production of milk proteins (Parry et al., 1987; Strange et al., 1991; Talhouk et al., 1992). Thus, alteration of the interaction between epithelium and its associated mesenchyme, which is an integral part of mammary involution, may also play a role in epithelial cell death. However, the epithelial-mesenchymal interactions that are the determining features in either mediating or modulating this cell death are just beginning to be defined. Stimuli that alter differentiated function may also induce apoptotic cell death of the epithelium but may have no physiological correlate. They may, however, have significant application in prevention or control of breast neoplasia.