Scientifically controlled field studies have established that parenterally administered killed vibrio vaccines or somatic antigen preparations offer only limited degrees of protection in certain population groups and have made it obvious that new approaches to the immunoprophylaxis of cholera are needed. It has now also been established that the symptoms of cholera result from the action of the cholera enterotoxin (choleragen) on the epithelial cells of the small intestine. Immulogically related enterotoxins have been incriminated in other newly recognized diarrheal diseases (e.g., those caused by Escherichia coli and "non-agglutinable" (NAG)vibrios). Additionally, volunteer studies have shown that induced cholera results in rather solid and lasting immunity against homologous re-challenge thus proving that immunity against cholera is feasible. Although numerous studies have demonstrated the efficacy of purely antitoxic immunity in experimental animal models, the protective effect of parenterally administered glutaraldehyde treated toxoid in man has shown to be limited, at best. The protection attained following an attack of cholera suggests that local immune mechanism may be of predominant importance. Immunity has been stimulated, experimentally in mice, by toxin antigen administered per os on a single occasion. Choleragenoid, which is non-toxic but binds to the same receptors as cholera toxin, has been shown to provide immediate resistance as well as later immunity to toxin challenge. More ideal, however, would be a colonizing mutant of V. cholerae which elaborates a non-toxic cross-reactive material (CRM) like choleragenoid and which could stimulate local antitoxic as well as anti-vibrio immune mechanisms. A tox-mutant of V. cholerae which is avirulent for man has been shown to elicit substantial immunity in man but the ideal CRM-mutant has yet to be found.