Individual predisposition to type 2 diabetes is influenced by the combined effect of a constellation of genetic variants and a multitude of environmental exposures. Identification of the specific genetic variants involved, and the mechanisms through which they operate, provides a powerful approach for delivering biological insights that can drive translational benefit, one that is already widely exploited in the personalised management of monogenic and syndromic forms of diabetes. This commentary develops the argument that equivalent translational advances for more common forms of diabetes are unlikely to result solely from the ability to define more complete individual inventories of genetic risk and environmental exposure. They will also require identification of complex molecular signatures able to provide integrative, empirical, longitudinal readouts of disease progression. These signatures will track causal mechanisms and capture an individual's position within a complex spectrum of pathophysiological processes, thereby supporting personalised approaches to intervention and treatment. This is one of a series of commentaries under the banner '50 years forward', giving personal opinions on future perspectives in diabetes, to celebrate the 50th anniversary of Diabetologia (1965-2015).