Oral rehydration solution (ORS) was established as the cornerstone of therapy for dehydration secondary to acute infectious diarrhea approximately 40 years ago. The efficacy of ORS is based on the ability of glucose to stimulate Na and fluid absorption in the small intestine via a cyclic AMP-independent process. Despite the establishment that ORS is the primary reason for the substantial reduction in morbidity and mortality from diarrhea in children in developing countries, the use of ORS has lagged for many reasons. This review highlights efforts to establish a major reformulation of ORS following the demonstration that short-chain fatty acids (SCFA) stimulate colonic Na and fluid absorption by a cyclic AMP-independent mechanism. The addition of high-amylose maize starch (HAMS), a microbially-fermentable (or 'resistant') starch, to ORS results in delivery of non-absorbed carbohydrate to the colon where it is fermented to SCFA. To date, three randomized controlled trials with a HAMS-ORS in south India have demonstrated a substantial decrease in diarrhea duration in both adults and children hospitalized for acute diarrhea. Significant efforts are now underway to establish this dual-action, modified HAMS-hypoosmolar ORS solution as the standard ORS for the treatment of dehydration from acute diarrhea.