Delirium is a common, costly, and potentially devastating condition for hospitalized older patients. Delirium is a multifactorial syndrome, involving the inter-relationship between patient vulnerability, or predisposing factors at admission, and noxious insults or precipitating factors during hospitalization. Through a series of studies, we first identified significant predisposing factors for delirium, including vision impairment, severe illness, cognitive impairment, and dehydration. Subsequently, significant precipitating factors were identified, including physical restraint use, malnutrition, adding more than three drugs, bladder catheter use, and any iatrogenic event. Through targeting preventive strategies towards six identified risk factors in a controlled clinical trial, we were successful in the primary prevention of delirium. In 852 subjects, the incidence of delirium was significantly reduced in the intervention group compared with usual care (9.9% vs 15.0%, matched odds ratio: 0.60; 95% confidence interval: 0.39-0.92). The total number of days and episodes of delirium were also significantly reduced in the intervention group. Based on this work, evidence-based recommendations for delirium prevention are proposed. While not all cases of delirium will be preventable with this approach, unifying medical and epidemiological approaches to delirium represents a key advance essential to reducing the high morbidity and mortality associated with delirium in the older population.