The antihistaminic drug ambodryl (Am) and the tranquillizer promazine (Pr), which had previously shown significant antimicrobial activities, were used to select bacterial mutants representing different levels of resistance to their action. These Am and Pr mutants were found to have simultaneously developed cross-resistance to penicillin (Pe), streptomycin (Sm), chloramphenicol (Cm), tetracycline (Tc) and kanamycin (Km). Certain first-step Am mutants of sensitive wild-type bacteria which were also sensitive to these antibiotics developed resistance to Pe and Sm as well as to Pr and the antihistamine benadryl (Bn). The next-step mutant of Am resistance not only doubled its resistance to these antibiotics and chemotherapeutics, but broadened its resistance-spectrum to cover Tc and Cm. These observations on cross-resistances seem to be best explained on the basis of a reduction in cell-membrane permeability acting in a nonspecific manner. The role of such cross-resistance in accounting for an overall increase in the minimum inhibitory concentrations (MIC) of many drugs against several groups of bacteria is evaluated.