The traditional view of innate immunity in insects is that every exposure to a pathogen triggers an identical and appropriate immune response, and that prior exposures to pathogens do not confer any protective (i.e. adaptive) effect against subsequent exposure to the same pathogen. This view has been challenged by experiments demonstrating that encounters with sub-lethal doses of a pathogen can prime the insect’s immune system and thus, have protective effects against future lethal doses. Immune priming has been reported across several insect species, including the red flour beetle, the honeycomb moth, the bumblebee, and the European honeybee, among others. Immune priming can also be trans-generational where the parent’s pathogenic history influences the immune response of its offspring. Phenotypic evidence of transgenerational immune priming (TGIP) exists in the tobacco moth Manduca sexta where first instar progeny of mothers injected with the bacterium Serratia marcescens exhibited a significant increase of in-vivo bacterial clearance. To identify the gene expression changes underlying TGIP in Manduca sexta, we performed transcriptome-wide, trans-generational differential gene expression analysis on mothers and their offspring after mothers were exposed to S. marcescens. We are the first to perform transcriptome-wide analysis of the gene expression changes associated with TGIP in this ecologically relevant model organism. We show that maternal exposure to both heat-killed and live S. marcescens has strong and significant trans-generational impacts on gene expression patterns in their offspring, including up-regulation of peptidoglycan recognition protein, toll-like receptor 9, and the antimicrobial peptide cecropin.