The capacity for active chloride secretion, thereby driving the secretion of fluid, is an important property of the intestinal epithelium. Chloride secretion is stimulated by mechanisms involving increases in either cyclic nucleotide or cytoplasmic calcium concentrations. The calcium-dependent response is transient and limited in its magnitude, implying that negative signaling events may restrict the overall extent of this mode of chloride transport. We have uncovered a number of negative signaling mechanisms intrinsic to the epithelium that uncouple increases in calcium from the downstream response of chloride secretion. These involve various kinase cascades, the generation of messengers derived from membrane phospholipids, and interactions of G protein-coupled receptors with those for peptide growth factors such as epidermal growth factor. This chapter will review emerging information on the details of these negative signaling mechanisms, as well as points of convergence and divergence. The possible physiological and pathophysiological significance of such signaling will also be discussed.