The recurring failure to translate neuroprotective strategies in animal models into clinical settings prompted us to reevaluate existing preclinical stroke models. One major issue in preclinical studies has been the lack of inclusion of prevalent risk factors in animal models of stroke. We have been addressing this issue by including hyperlipidemia and diabetes, prevalent co-morbid conditions, in our experimental model of stroke. We reported that animals with these risk factors displayed increased peripheral inflammation and resulted in exacerbation of ischemic brain injury. Our contributions from these studies to the stroke field are the demonstration of comorbidity-modified inflammation and injury in ischemic stroke.