OBJECTIVE Depression is associated with the onset of type 2 diabetes. A systematic review and meta-analysis of observational studies, controlled trials, and unpublished data was conducted to examine the association between depression and insulin resistance (IR). RESEARCH DESIGN AND METHODS Medline, EMBASE, and PsycINFO were searched for studies published up to September 2011. Two independent reviewers assessed the eligibility of each report based on predefined inclusion criteria (study design and measure of depression and IR, excluding prevalent cases of diabetes). Individual effect sizes were standardized, and a meta-analysis was performed to calculate a pooled effect size using random effects. Subgroup analyses and meta-regression were conducted to explore any potential source of heterogeneity between studies. RESULTS Of 967 abstracts reviewed, 21 studies met the inclusion criteria of which 18 studies had appropriate data for the meta-analysis (n = 25,847). The pooled effect size (95% CI) was 0.19 (0.11–0.27) with marked heterogeneity (I2 = 82.2%) using the random-effects model. Heterogeneity between studies was not explained by age or sex, but could be partly explained by the methods of depression and IR assessments. CONCLUSIONS A small but significant cross-sectional association was observed between depression and IR, despite heterogeneity between studies. The pathophysiology mechanisms and direction of this association need further study using a purposively designed prospective or intervention study in samples at high risk for diabetes.