Water-seeded and continuously flooded rice in California is mostly grown as a continuous crop and weeds are the most serious rice production problem. Echinochloa phyllopogon (Stapf) Koss and Cyperus difformis L. are adapted to this aquatic system and compete with rice, causing heavy economic losses. Flooding cannot fully suppress these weeds. Heavy reliance on few available herbicides resulted in the evolution of herbicide resistance in populations of both weeds in California rice fields. Resistance to bensulfuron-methyl (ALS inhibitor) is widespread among C. difformis populations. E. phyllopogon has evolved resistance to several herbicides, including bispyribac-sodium (ALS inhibitor), which has not yet been commercially used. A resistant (R) E. phyllopogon was also much more tolerant to bensulfuronmethyl than a susceptible (S) biotype. Understanding the patterns and mechanisms of cross-resistance in key weeds of rice to bensulfuron-methyl and bispyribac-sodium is relevant for the successful deployment of this new herbicide and for the management of herbicide resistance in California rice. Whole-plant bioassays were conducted to compare responses between E. phyllopogon and C. difformis to bispyribac-sodium and bensulfuron-methyl and to detect the involvement of cyt P-450 monooxygenases in E. phyllopogon resistance to bensulfuron-methyl using the cyt P-450 inhibitors piperonyl butoxide and malathion (previous studies had already shown cyt P-450-mediated resistance to bispyribac-sodium). ALS activity was assayed on leaf extracts from young R and S plants of both species for a range of bispyribac-sodium and bensulfuron- methyl concentrations. The dose–response studies confirmed cross-resistance in R E. phyllopogon; minimum and maximum ratios (R/S) of the GR50 values of resistant to susceptible plants were 9 and >25.5 for bispyribac-sodium and bensulfuron-methyl, respectively. cyt P-450 contributed to bensulfuron-methyl resistance in R E. phyllopogon. C. difformis was also cross-resistant (R/S ratios: >10 for bispyribac-sodium and >26 for bensulfuron-methyl). ALS assays demonstrated that, unlike R E. phyllopogon, cross-resistance in R C. difformis was due to reduced ALS sensitivity. C. difformis ALS was more sensitive to bispyribac-sodium ðI50 ¼ 138:87nMÞ than to bensulfuron-methyl ðI50 ¼ 6724:56nMÞ. Also, ALS inhibition in R and S E. phyllopogon was higher with bispyribac-sodium. Thus, binding differences between both herbicides at the target-site are suggested. This study reveals that cross-resistance between bensulfuron-methyl and bispyribac-sodium in both weeds involves degradation enhancement through monooxygenases and target-site alteration.