Herbicide resistance is increasing in incidence among weed populations and poses a threat to food security. In Sunflower County, MS, a population of junglerice was identified with resistance to four herbicides, fenoxaprop-P-ethyl, imazamox, quinclorac, and propanil, each representing a different mechanism of action. The target site of fenoxaprop-P-ethyl, acetyl coenzyme A carboxylase (ACCase), was investigated. The ACCase contained none of the known resistance-conferring point mutations and an enzyme assay revealed no difference in response to increasing levels of fenoxaprop-P-ethyl between the resistant biotype and a sensitive biotype, indicating that the ACCase enzyme in the resistant biotype was sensitive to the herbicide. Whole-plant dose response assays in the presence and absence of cytochrome P450 and glutathione-S-transferase (GST) inhibitors did not increase efficacy of fenoxaprop-P-ethyl in the resistant biotype. However, when malathion, a cytochrome P450 inhibitor, was applied with imazamox or quinclorac, a reduction in resistance was observed in the resistant biotype, suggesting that a cytochrome P450 was important to the resistance mechanism for these two herbicides. RNA was isolated from the resistant and sensitive biotypes before and one hour after imazamox treatment for RNA-seq analysis. The reads from all samples were pooled to assemble the first E. colona leaf transcriptome. Differential gene expression analysis comparing untreated and treated samples for both biotypes revealed that several stress response genes were upregulated following herbicide exposure. A time course examining six of these genes showed that expression peaked between 4 and 12 hours and then dropped to untreated levels by 48 hours. Comparison of untreated resistant and sensitive plants revealed that a kinase and GST were significantly upregulated in the resistant biotype and an F-box protein was significantly downregulated. SNP analysis of cytochrome P450 sequences identified several nonsynonymous point mutations of interest including two transcripts that had premature stop codons in the sensitive but not the resistant biotype. These transcripts and their products should be the subject of future studies to determine if and how they are involved in resistance.