The rectal gland of the spiny dogfish shark, Squalus acanthias, secretes chloride by a furosemide sensitive process that has been termed "secondary active." Chloride enters the cell across the basolateral cell membrane via the sodium:potassium:2 chloride cotransporter. The energy for this electroneutral uptake step is provided by the electrochemical gradient for sodium directed into the cell. This is maintained by Na-K-ATPase present in the basolateral cell membrane. Present as well in the basolateral cell membrane is a potassium conductance that permits potassium to exit passively. Chloride leaves the cell across the luminal membrane via a chloride conductance closely similar to CFTR. The rectal gland is thus a model for the mechanism of secondary active chloride transport utilized by various epithelial organs throughout the vertebrate kingdom. This report reviews the humoral agents that regulate the secretion of chloride by the rectal gland and the intracellular mechanisms that mediate it. CNP, released from the heart in response to a volume stimulus, causes the release of VIP from nerves within the gland and together with VIP directly activates the rectal gland cell.