Acid secretion by the gastric parietal cell is regulated by paracrine, endocrine, and neural pathways. The physiological stimuli include histamine, acetylcholine, and gastrin via their receptors located on the basolateral plasma membranes. Stimulation of acid secretion typically involves an initial elevation of intracellular calcium and/or cAMP followed by activation of a cAMP-dependent protein kinase cascade that triggers the translocation and insertion of the proton pump enzyme, H,K-ATPase, into the apical plasma membrane of parietal cells. Whereas the H,K-ATPase contains a plasma membrane targeting motif, the stimulation-mediated relocation of the H,K-ATPase from the cytoplasmic membrane compartment to the apical plasma membrane is mediated by a SNARE protein complex and its regulatory proteins. This review summarizes the progress made toward an understanding of the cell biology of gastric acid secretion. In particular we have reviewed the early signaling events following histaminergic and cholinergic activation, the identification of multiple factors participating in the trafficking and recycling of the proton pump, and the role of the cytoskeleton in supporting the apical pole remodeling, which appears to be necessary for active acid secretion by the parietal cell. Emphasis is placed on identifying protein factors that serve as effectors for the mechanistic changes associated with cellular activation and the secretory response.