We studied the relationship between the use of three detoxification pathways and urine pH and the tolerance of desert woodrats from two populations to a mixture of naturally occurring plant secondary metabolites (mostly phenolics) in resin from creosote bush (Larrea tridentata). The two populations of desert woodrats came from the Mojave desert (Mojave woodrats), where woodrats consume creosote bush, and from the Great Basin desert (Great Basin woodrats), where the plant species is absent. We fed woodrats alfalfa pellets containing increasing levels of the phenolic resin and measured three detoxification pathways and urine pH that are related to detoxification of allelochemicals. We found that the excretion rate of two phase II detoxification conjugates, glucuronides and sulfides. increased with increasing resin intake, whereas excretion of hippuric acid was independent of resin intake, although it differed between populations. Urine pH declined with increasing resin ingestion. The molar proportion of glucuronides in urine was three times that of the other conjugates combined. Based on an evaluation of variation in the three detoxification pathways and urine pH in relation to resin intake, we rejected the hypotheses that woodrats' tolerance to resin intake is related to capacity for amination, sulfation, or pH regulation. However, Mojave woodrats had higher maximum glucuronide excretion rates, and we accepted the hypothesis that within and between populations woodrats tolerate more resin because they have a greater capacity for glucuronide excretion.