Achalasia is a rare but important condition affecting the myenteric neurons of the esophagus. A number of studies have provided evidence for the preservation of cholinergic innervation to the esophagus in achalasia. This forms the rationale for the treatment of achalasia with botulinum toxin. Identification of nitric oxide as the primary inhibitory neurotransmitter of the gastrointestinal tract has improved our understanding of the pathophysiology of primary achalasia. Neurons containing nitric oxide are absent within the myenteric plexuses of patients with achalasia, and the experimental inhibition of nitric oxide produces a picture that manometrically mimics achalasia. Recent advances have provided insights into the genetic basis and pathogenesis of a growing number of secondary forms of achalasia. Examples of such secondary disorders include Allgrove's syndrome, autoimmune polyglandular syndrome, and multiple endocrine neoplasia type 2B.