The potential to undertake truly Genome-Wide Association (GWA) analyses in large, well-characterized subject samples is generating a stream of novel disease-susceptibility genes, highlighting new aetiological pathways and revealing new ways of understanding the molecular basis of human health and disease. However, this acceleration represents a vivid contrast to the very slow progress which characterized the field of complex trait genetics until recently.   Three major developments have contributed to the recent transformation of the prospects for complex trait gene identification. First, the human genome sequence and HapMap have transformed understanding of the patterns of genome sequence landscape and variation in human populations. Second, rapid advances in genotyping capabilities have made it possible to assay at affordable cost, most genome sequence variation attributable to common single-nucleotide polymorphisms (SNPs). Third, a more realistic understanding of the scale of likely effect sizes has fostered accrual and analysis of larger sample sets.   These exciting developments have generated a great deal of optimism and promise novel insights into the aetio-pathogenesis of complex traits. However, there is, at the same time, a growing realization that existing efforts are only capable of detecting the ‘low hanging fruit’. In other words, that the power of individual GWA scans to detect aetiological variants is limited to relatively large effect sizes.   The ENGAGE project will make a substantial and unique contribution to the identification and characterization of variants and genetic profiles behind complex diseases and their trait components as well as in estimation of their relationship with lifestyle risk factors.