The metabolic overlap syndromes hyperlipidaemia, diabetes mellitus, insulin resistance, obesity and hypertension together constitute the major risk factors for coronary heart disease. The genetic predisposition to these conditions is strong but complex, and many of the genes involved have not been identified. The identification of the genes or metabolic pathways involved in these disorders would lead to new diagnostic and therapeutic targets with wide applicability. The spontaneously hypertensive rat (SHR) is a model of essential hypertension which also displays abnormalities of lipid metabolism and insulin resistance similar to those found in the human metabolic syndromes. These include raised blood triglycerides and fatty acids, defective catecholamine-mediated lipolysis and excessive growth of intra-abdominal adipocytes. Similar abnormalities have been identified in combined hyperlipidaemia, maturity-onset diabetes mellitus and obesity in humans. We are using the SHR as a model to identify genes and pathways that are likely to be in common with those causing the human diseases. Quantitative trait loci (QTL) for glucose and fatty acid metabolism, hypertriglyceridaemia and hypertension map to a locus on rat chromosome 4. We used cDNA microarrays, congenic strains and radiation hybrid mapping to identify a defective gene, Cd36 (encoding fatty acid translocase), at the peak of linkage. Cd36 cDNA contains multiple sequence variants and the encoded protein product is undetectable in SHR adipocyte plasma membrane. Transgenic mice overexpressing Cd36 have reduced blood lipids. We conclude Cd36 deficiency underlies insulin resistance, defective fatty acid metabolism and hypertriglyceridaemia in SHR (ref. 1). Human CD36 is being examined for mutation in subjects with insulin resistance from different ethnic backgrounds. The role of other genes showing primary or secondary alteration in expression and their role in metabolic pathway tracking (‘pathwayomics’) and QTL identification will be discussed.