Feed efficiency phenotypes defined by genotypes or gene markers are unknown. To date, there are only limited studies on global gene expression profiling on feed efficiency. The objective of this study was to identify genes and pathways associated with residual feed intake (RFI) through transcriptional profiling of duodenum at two different ages in a chicken population divergently selected for low (LRFI) or high (HRFI) RFI. The global gene expression differences in LRFI and HRFI were assessed by the Affymetrix GeneChip(®) Chicken Genome Array and RT-PCR using duodenal tissue on days 35 and 42. The Ingenuity Pathway Analysis program was used to identify canonical and gene network pathways associated with RFI. A global view of gene expression differences between LRFI and HRFI suggest that RFI can be explained by differences in cell division, growth, proliferation and apoptosis, protein synthesis, lipid metabolism, and molecular transport of cellular molecules. Chickens selected for improved RFI achieve efficiency by reducing feed intake with a nominal or no change in weight gain by either up-regulating CD36, PPARα, HMGCS2, GCG or down-regulating PCSK2, CALB1, SAT1, and SGK1 genes within the lipid metabolism, small molecule biochemistry, molecular transport, cell death, and protein synthesis molecular and cellular functions. Chickens selected for reduced RFI via reduced feed intake with no change in weight gain achieve feed efficiency for growth by the up-regulation of genes that reduce appetite with increased cellular oxidative stress, prolonged cell cycle, DNA damage, and apoptosis in addition to increased oxidation of dietary fat and efficient fatty acids transported from the intestines.