The role of mucin 1 (MUC1) in protecting epithelia from microbial infection, enzymatic digestion, and other irritants has been appreciated for some time. In addition, MUC1 serves as a barrier to embryo implantation. MUC1 is highly abundant in many tumors in which its role in barrier function may serve to protect cells from the host immune system, whereas MUC1 is less abundant in certain other cells-for example, in trophoblasts and hematopoietic cells. Most of the functions of MUC1 depend upon its large, extracellular ectodomain. Nonetheless, a series of studies have demonstrated a surprisingly diverse role for the small, highly conserved cytoplasmic domain of MUC1 in intracellular signaling. These intracellular activities have potential roles in the physiology of both malignant and nonmalignant cells.