Improving the feeding efficiency of dairy cows is a key component to improve the utilization of land resources and meet the demand for high-quality protein. Advances in genomic methods and omics techniques have made it possible to breed more efficient dairy cows through genomic selection. The aim of this review is to obtain a comprehensive understanding of the biological background of feed efficiency (FE) complex traits in purebred Holstein dairy cows including heritability estimate, and genetic markers, genes, and pathways participating in FE regulation mechanism. Through a literature search, we systematically reviewed the heritability estimation, molecular genetic markers, genes, biomarkers, and pathways of traits related to feeding efficiency in Holstein dairy cows. A meta-analysis based on a random-effects model was performed to combine reported heritability estimates of FE complex. The heritability of residual feed intake, dry matter intake, and energy balance was 0.20, 0.34, and 0.22, respectively, which proved that it was reasonable to include the related traits in the selection breeding program. For molecular genetic markers, a total of 13 single-nucleotide polymorphisms and copy number variance loci, associated genes, and functions were reported to be significant across populations. A total of 169 reported candidate genes were summarized on a large scale, using a higher threshold (adjusted P value < 0.05). Then, the subsequent pathway enrichment of these genes was performed. The important genes reported in the articles were included in a gene list and the gene list was enriched by gene ontology (GO):biological process (BP), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways analysis. Three GO:BP terms and four KEGG terms were statistically significant, which mainly focused on adenosine triphosphate (ATP) synthesis, electron transport chain, and OXPHOS pathway. Among these pathways, involved genes such as ATP5MC2, NDUFA, COX7A2, UQCR, and MMP are particularly important as they were previously reported. Twenty-nine reported biological mechanisms along with involved genes were explained mainly by four biological pathways (insulin-like growth factor axis, lipid metabolism, oxidative phosphorylation pathways, tryptophan metabolism). The information from this study will be useful for future studies of genomic selection breeding and genetic structures influencing animal FE. A better understanding of the underlying biological mechanisms would be beneficial, particularly as it might address genetic antagonism.© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society of Animal Science.JiangWentaoW0009-0005-8398-3122Institute for Global Food Security, School of Biological Sciences, Queen's University Belfast, Belfast, BT9 5DL, UK.Agri-Food and Biosciences Institute, Large Park, Hillsborough, BT26 6DR, UK.MooneyMark HMH0000-0002-3600-341XInstitute for Global Food Security, School of Biological Sciences, Queen's University Belfast, Belfast, BT9 5DL, UK.ShiraliMasoudM0000-0002-5401-0541Institute for Global Food Security, School of Biological Sciences, Queen's University Belfast, Belfast, BT9 5DL, UK.Agri-Food and Biosciences Institute, Large Park, Hillsborough, BT26 6DR, UK.eng202310080003China Scholarship Council (CSC)Systematic ReviewMeta-AnalysisJournal ArticleUnited StatesJ Anim Sci80030020021-88120Genetic MarkersIMFemaleCattlegeneticsAnimalsLactationgeneticsGenetic MarkersPhenotypeGenomeEatinggeneticsAnimal FeedMilkmetabolismA thorough understanding of the genetic factors that influence the feed efficiency of dairy cows is a prerequisite for planning and implementing selective breeding programs. Therefore, a systematic review of reported heritability, genetic markers, and biological pathways affecting FE-related traits in Holstein dairy cows was conducted and followed by a meta-analysis. A total of 47 articles were refined after literature screening and were presented in this review. A meta-analysis based on a random-effects model was then performed to combine the heritability estimates from studies. The meta-analysis showed heritability estimates of residual feed intake, dry matter intake, and energy balance were 0.22, 0.34, and 0.24, respectively. The systematic review demonstrated that 169 significant candidate genes, 13 genetic markers, and 29 biological mechanisms were previously reported on FE in Holstein dairy cows. Involved candidate genes and biological mechanisms are presented mainly in four biological mechanisms (insulin-like growth factors axis, lipid metabolism, oxidative phosphorylation pathways, tryptophan metabolism). The meta-analysis of the reported candidate genes showed three statistically significant KEGG terms and four GO:BP terms, which mainly focused on ATP synthesis, electron transport chain, and OXPHOS pathway.