In both spontaneous and iatrogenic Cushings syndrome, chronic glucocorticoid excess causes obesity, hyperglycaemia, hypertension and accelerated cardiovascular disease. We have pursued the global hypothesis that elevation of cortisol causes cardiovascular disease in the general population, and that the underlying mechanisms will reveal new therapies for cardiometabolic diseases. Circumstantial support is provided by cohort studies, in which higher plasma cortisol is associated with cardiovascular risk factors and is predictive of subsequent cardiovascular disease. To test causality, however, requires either intervention studies or identification of genetic determinants of cortisol. To explore genetic variants associated with cortisol we established the CORtisol NETwork (CORNET) consortium. Using the relatively crude but widely available and heritable trait of morning plasma cortisol the most recent CORNET genome wide association meta-analysis of >7 M SNPs in nearly 25 000 people has identified only one influential locus, spanning the SERPINA6 and SERPINA1 genes which encode for corticosteroid binding globulin (CBG) and alpha1-antitrypsin (AAT), respectively. Mendelian randomisation analysis reveals that cortisol-associated SNPs are also associated with cardiovascular disease (in UK Biobank and CARDIOGRAMplusC4D), providing evidence that elevated cortisol is causative for cardiovascular disease. Identifying genetic variants which influence cortisol has also provided insights into cortisol biology. Recent eQTL analysis in 7 tissues from 600 subjects has shown that SNPs in SERPINA6 which predict higher cortisol are associated not only with increased CBG expression in liver but also with networks of altered glucocorticoid-regulated gene expression in adipose tissue. This indicates that CBG influences the delivery of cortisol to peripheral tissues. One mechanism for this may involve cleavage of CBG by neutrophil elastase within adipose tissue, a process which is inhibited by AAT. Targeting these pathways may yet provide new approaches that can be tested in intervention studies to prevent cardiometabolic disease.