Leafy spurge (Euphorbia esula) is an invasive perennial rangeland weed. Some evidence suggests that the introduction of the most invasive genotypes in the Great Plains originated from Eastern Europe (likely with immigrants from Russia and the Ukraine in the late 1880’s). We collected leaf material from multiple plants from 4 different populations growing wild in the US near Fargo ND and the Ukraine near Kiev, and subjected the material to microarray analysis using the leafy spurge 23K cDNA arrays. Microarray analysis identified 143 genes that were significantly differentially expressed at a p value of less than 0.005 and 1349 genes were differentially expressed using a p value cutoff of 0.05. Gene set and sub-network enrichment analysis clearly identified processes associated with pathogen responses were up-regulated in Ukrainian samples, and pathways and signals associated with growth and photosynthesis were up-regulated in US samples. These results suggest the increase in aggressive growth in US populations may result from reduction in biotic stress responses due to fewer or less intense pathogen attacks in the invaded range (consistent with an Enemy Release Hypothesis). However, genetic differences resulting from evolutionary pressure cannot be ruled out.