The current classification of diabetes had its genesis over 85 years ago, when individuals with diabetes were first subclassified into insulin sensitive and insulin insensitive states based on the response to an oral glucose tolerance test. About 35 years later, the contemporary classifications of type 1 and type 2 diabetes were coined. Today's evidence, however, suggests that multiple etiologic and pathogenic processes lead to both type 1 and type 2 diabetes, reflecting significant heterogeneity in factors associated with initiation, progression, and clinical presentation of each disorder of glucose homeostasis. Further, the current classification fails to recognize what is currently defined as "atypical" diabetes. Heterogeneity of diabetes continues through the life-course of an individual, with modification of prognosis risk (eg, diabetic complications) altered by genetics, life experience, comorbidities, and therapy. Understanding the sources of heterogeneity in diabetes will likely improve diagnosis, prevention, treatment, and prediction of complications in both the medical and public health settings. Such knowledge will help inform progress in the emerging era of precision diabetes medicine. This article presents NIDDK's Heterogeneity of Diabetes Initiative and a corresponding roadmap for future research in type 2 diabetes heterogeneity.