Glucose absorption by the small intestine has been studied for nearly a century. Despite extensive knowledge about the identity, functioning and regulation of the relevant transporters, there has been and there remains controversy about how these transporters work in concert to determine the overall epithelial absorption of key nutrients (e.g. sugars, amino acids) over a wide range of dietary and/or luminal concentrations. Our broader, integrative understanding of intestinal absorption requires more than the reductionist dissection of all the components and their elaboration at molecular and genetic levels. This Commentary emphasizes the integration of discrete molecular players and processes (including paracellular absorption) that, in combination, determine the overall epithelial absorption of key nutrients (e.g. sugars, amino acids) and putative anti-nutrients (water-soluble toxins), and the integration of that absorption with other downstream processes related to metabolic demands. It identifies historic key advances, controversies and future research ideas, as well as important perspectives that arise through comparative as well as biomedical physiological research.