OBJECTIVE To identify the clinical and genetic factors that explain why the rate of diabetes progression is highly variable between idividuals following diagnosis of type 2 diabetes. RESEARCH DESIGN AND METHODS We studied 5,250 patients with type 2 diabetes using comprehensive electronic medical records in Tayside, Scotland, from 1992 onward. We investigated the association of clinical, biochemical, and genetic factorswith the risk of progression of type 2 diabetes fromdiagnosis to the requirement of insulin treatment (defined as insulin treatment or HbA1c 8.5% [69 mmol/mol] treated with two or more noninsulin therapies). RESULTS Risk of progression was associated with both low and high BMI. In an analysis stratified by BMI and HbA1c at diagnosis, faster progression was independently associated with younger age at diagnosis, higher log triacylglyceride (TG) concentrations (hazard ratio [HR] 1.28 permmol/L [95% CI 1.15-1.42]) and lower HDL concentrations (HR 0.70 permmol/L [95% CI 0.55-0.87]). A high Genetic Risk Score derived from 61 diabetes risk variants was associated with a younger age at diagnosis and a younger age when starting insulin but was not associated with the progression rate from diabetes to the requirement of insulin treatment. CONCLUSIONS Increased TG and lowHDL levels are independently associated with increased rate of progression of diabetes. The genetic factors that predispose to diabetes are different from those that cause rapid progression of diabetes, suggesting a difference in biological process that needs further investigation.