This review examines signal transduction pathways mediating agonist-induced contraction of circular muscle in the body of the esophagus and in the lower esophageal sphincter (LES). In the LES, circular muscle agonists activate a well-defined contractile pathway, involving calcium (Ca²⁺)-induced activation of calmodulin and myosin kinase, causing phosphorylation of 20-kDa myosin light chains (MLCs) and contraction. In this pathway, phosphorylation and contraction may be modulated by other factors, resulting, for instance, in inhibition of phosphatase activity, which may potentiate MLC phosphorylation. The agonist-activated contractile pathway of circular muscle from the esophageal body is not as well defined, and it is different from the LES contractile pathway, as it depends on activation of a Ca²⁺-independent protein kinase C (PKC), PKC-ϵ. In this pathway, agonist-induced Ca²⁺ influx and/or release activate phospholipases to produce second messengers, such as diacylglycerol and arachidonic acid. The second messengers, however, activate a PKC-ϵ and a contractile pathway, which is Ca²⁺ independent. This contractile pathway depends on activation of the mitogen-activated protein (MAP) kinases ERK1 and ERK2 and of p38 MAP kinase. These kinases are, in turn, linked to the small heat-shock protein HSP27, to integrin-linked kinase, and perhaps to other Ca²⁺-independent kinases, such as zipper kinase capable of producing MLC phosphorylation and contraction.