OBJECTIVE—The aim was to assess the relationship between adipokines, including interleukin (IL)-6, leptin, and adiponectin, with development of type 2 diabetes and assess the role of obesity and insulin resistance in these relationships. RESEARCH DESIGN AND METHODS—We conducted a prospective study of 3,599 nondiabetic men aged 60–79 years and followed up for a mean period of 5 years, during which time there were 108 incident cases of type 2 diabetes. RESULTS—Elevated IL-6, leptin, and low adiponectin were associated with increased risk of type 2 diabetes even after adjustment for BMI, lifestyle factors, preexisting cardiovascular disease, and systolic blood pressure. The relative risks (RRs) (top vs. bottom third) were 2.02 (95% CI 1.14–3.58) for IL-6, 1.91 (0.97–3.76) for leptin, and 0.40 (0.23–0.70) for adiponectin. Further adjustment for insulin resistance made minor differences to the IL-6 diabetes relationship (adjusted RR 2.12 [1.18–3.81]), weakened the associations with adiponectin (0.59 [0.33–1.04]), and abolished the association between leptin and diabetes (1.12 [0.55–2.26]). The inverse relation between low adiponectin and diabetes was significantly stronger in men who were obese (waist circumference >102 cm or BMI ≥30 kg/m2) (0.30 [0.11–0.79]) relative to leaner men (0.93 [0.44–1.96]) (test for interaction P = 0.04). CONCLUSIONS—The association between leptin and incident diabetes is mediated by insulin resistance. By contrast, the positive association between IL-6 and diabetes appeared to be independent of obesity and insulin resistance. Finally, the association between low adiponectin and increased risk of diabetes appears to be significantly stronger in obese men than in leaner counterparts.