Diarrheal diseases are among the most devastating illnesses globally, but the introduction of oral rehydration therapy has reduced mortality due to diarrhea from >5 million children, under the age of 5, in 1978 to 1.3 million in 2002. Variations of this simple therapy of salts and sugars are prevalent in traditional remedies in cultures world-wide, but only in the past four decades have the scientific bases for these remedies begun to be elucidated. This review aims to provide a broad understanding of the cellular basis of oral rehydration therapy. The features integral to the success of oral rehydration therapy are active glucose transport in the small intestine, commensal bacteria, and short-chain fatty acid transport in the colon. The review examines these processes and their regulation and considers new approaches that might supplement oral rehydration therapy in controlling diarrheal diseases.