Phosphine gas protects global grain reserves from pest insects, which are increasingly resistant. We identified dihydrolipoamide dehydrogenase (DLDH) as the enzyme responsible for phosphine resistance and characterised in C. elegans the toxic action of phosphine and the resistance mechanisms with NMR-based metabolomics [1]. We present progress we have made over the past years in elucidating the role of DLDH in phosphine resistance and general metabolic regulation. Recent detailed characterization of the phosphine response shows that DLDH preadapts C. elegans to phosphine toxicity by triggering global metabolic suppression in the resistant nematode strain [2]. DLDH is a core metabolic enzyme, central to metabolic regulation, and a new class of resistance factor. DLDH participates in four key steps of core metabolism, which are affected differently by phosphine in mutant and wild-type animals. This position of DLDH in the metabolic network makes it a highly likely candidate for a central regulator of metabolism. We are now studying the role of DLDH in biological/clinical processes, such as lifespan determination, obesity, Alzheimer’s Disease, and respiration. Metabolomic analysis indicates a role for DLDH in the cross-talk between branched-chain amino acid and lipid metabolism that is important in the development of obesity. In addition, we have developed CeCon, a genome-scale metabolic model of C. elegans metabolism that enables further characterization of DLDH’s role in these processes through computational modelling of the nematode’s metabolism [2]. CeCon comprises 225 pathways, 1923 reactions, 1394 metabolites and 73 transporters. The model forms the basis for creating a C. elegans consensus genome-scale model as part of a multinational consortium [3]. DLDH is an exceptional case in which a combination of systems biology methods has identified a single genetic cause of phenotypic change that can subsequently be studied with a wide range of methods from classical biochemistry to systems biology.