The mechanisms behind nutrient uptake in adults are reasonably well understood, but knowledge of gut function in newborns is less clear. Now, Terry Lechler and colleagues investigate the role of two transcription factors, MAFB and c-MAF (Mafs), during neonate intestinal development in mice. Using immunostaining and genetic approaches, the authors show that Maf-positive cells emerge during early enterocyte specification, but do not contribute to the adult stem cell population in intestinal crypts. Through multi-omic approaches, the researchers reveal that Maf expression is directly regulated by HNFα/γ transcription factors. Maf double knockout results in weight loss, specifically in neonates, and RNA-sequencing determines that Mafs induce the expression of phagocytic, endocytic and lysosomal genes required for macromolecule nutrient uptake. Indeed, the mutants fail to absorb labelled protein and dextran, and instead display increased lipid metabolism and expression of adult enterocyte genes, indicative of metabolic compensation. Interestingly, many differentially regulated genes in Maf-factor double mutants overlap with differentially regulated genes in Prdm1-deficient intestines, suggesting parallel roles. Prdm1 knockouts have a similar phenotype to the Maf double mutants, which supports this hypothesis. Together, these data begin to reveal the gene regulatory networks that control nutrient absorption in neonates.