Uncoupler resistance presents a potential challenge to the conventional chemiosmotic coupling mechanism. In E. coli, an adaptive response to uncouplers was found in cell growing under conditions requiring oxidative phosphorylation. It is suggested that uncoupler-resistant mutants described in the earlier literature might represent a constitutive state of expression of this "low energy shock" adaptive response. In the environment, bacteria are confronted by nonclassical uncoupling factors such as organic solvents, heat, and extremes of pH. It is suggested that the low energy shock response will aid the cell in coping with the effects of natural uncoupling factors. The genetic analysis of uncoupler resistance has only recently began, and is yielding interesting and largely unexpected results. In Bacillus subtilis, a mutation in fatty acid desaturase causes an increased content of saturated fatty acids in the membrane and increased uncoupler resistance. The protonophoric efficiency of uncouplers remains unchanged in the mutants, inviting nonorthodox interpretations of the mechanism of resistance. In E. coli, two loci conferring resistance to CCCP and TSA were cloned and were found to encode multidrug resistance pumps. Resistance to one of the uncouplers, TTFB, remained unchanged in strains mutated for the MDRs, suggesting a resistance mechanism different from uncoupler extrusion.