Natriuretic peptides interact with two general types of receptors, particulate guanylyl cyclases and natriuretic peptide C receptors. The latter are considered clearance receptors, whereas the former are thought to mediate biological effects of natriuretic peptides. Clearance receptors typically are perceived to function merely as transport proteins to facilitate the entry of a molecule into a cell. However, a number of natriuretic peptide actions are mimicked by selective natriuretic peptide C receptor ligands. These pharmacological data are intriguing but the conclusions depend on the absolute specificity of the ligands for the natriuretic peptide C receptor. A novel approach to this problem of specificity utilized cytosolic regions of the receptor to test if they mimicked activation of the natriuretic peptide C receptor. Recent studies indicated that these cytosolic fragments mimic natriuretic peptide C receptor stimulation, as measured by reduced adenylyl cyclase activity in, and neurotransmitter efflux from, premeabilized cells. Futhermore, the region of the receptor mediating the suppression of adenylyl cyclase activity was distinct from the region mediating the suppression of neurotransmitter efflux. The cytosolic region of the natriuretic peptide C receptor consists of only 37 amino acids; therefore, this dichotomy of function was unanticipated. The convergence of evidence using specific receptor ligands and natriuretic peptide C recptor fragments provides overwhelming evidence favoring a signal-transducing role for the natriuretic peptide C receptor. This conclusion is in stark contrast to the predominant view of this receptor as a clearance receptor with no signal-transducing role. Coincidentally, the low density lipoprotein receptor has been recognized recently as mitogenic entity and the mitogenic effect is blocked by pertussis toxin pretreatment. Thus, the relegation of clearance receptors to a non-signaling role could represent a widespread error.