Summary: Type II diabetes is a common, complex and heterogeneous group of disorders of growing public health concern. Paradoxically, rare monogenic forms of diabetes mellitus have been the most informative regarding diabetes pathophysiology to date. We discuss disappointing results of genetic approaches thus far, emphasizing the genetic heterogeneity underlying the common phenotypic endpoint of elevated blood glucose level and the phenotypic misclassification in large studies resulting from this admixture and from the obligatory use of epidemiological or clinical surrogate measures. We suggest that novel approaches that take explicit account of the phenotypic, environmental and genetic complexities of type II diabetes are needed and discuss some principles that might underlie such approaches.