Clinical nutrition is an integrative science with the ultimate purpose of defining in quantitative terms the characteristics of an optimum nutritional intake in relation to a defined level of nutritional health. Thus, to achieve major progress in our field of clinical nutrition, data from the molecular, subcellular, cellular, and organ levels need to be exploited and considered in reference to the whole organism; this requires that we identify important unanswered questions for this latter and more complex, hierarchical level of biological organization and then pursue the answers with the aid of techniques and approaches used in and concepts emerging from all areas of modern biology. In relation to this, the present overview of some of the studies that my colleagues, my students, and I have conducted was meant to emphasize that there is considerable merit in attempting to explore the integrative aspects of the physiology and biochemistry of human nutrient metabolism, specifically of amino acids, with the aid of stable-isotope probes. Recognition of the importance of the phosphorylation and dephosphorylation of cellular proteins as a major regulatory process and of the regulation of leucine oxidation through changes in the activity of the branched-chain 2-Oxo acid dehydrogenase complex via a reversible phosphorylation catalyzed by a specific branched-chain dehydrogenase kinase and phosphatase is indeed exciting new knowledge. Following from this, Espinal et al state: "The activity of the complex determines the rate of degradation and the dietary requirement for branched-chain amino acids." However, the physiological situation cannot be appreciated simply in these terms because we showed that the rate of oxidation of leucine depends upon the tissue availability of the amino acid. Furthermore, our studies revealed that the regulation of leucine oxidation in the intact human appears to be achieved through biochemical mechanisms that are linked to the host's nutritional requirements. These observations and interpretations would not have emerged by considering only the enzymology of branched-chain amino acid metabolism; this underscores the value of exploring, through use of safe noninvasive tracer techniques, the communication of amino acid metabolism among different systems and how these systems might interplay to influence the nutritional needs of the individual. This recalls Fishman's advice: "Physiology has a special role to play here, for after probing the submicroscopic, life is left behind. It is physiology's responsibility to put together the lifeless pieces of the molecular biologist into living systems."(ABSTRACT TRUNCATED AT 400 WORDS)