Discharge out of the hospital is a time of heightened vulnerability for our patients. The combination of shorter lengths of stay and increased clinical acuity results in increased complexity of discharge instructions and higher expectations for patients to perform challenging self-care activities. Yet, the amount of time and resources available for patient and family caregiver preparation prior to discharge has not significantly changed commensurate with these new demands. Inadequate health literacy and unrecognized cognitive impairment are two important contributing factors. In this article we discuss the effects of health literacy and cognitive impairment on patient comprehension of discharge instructions, how this may impact the frequency of adverse events after they leave the hospital, and likelihood of readmission, and offer an evidence-based prototype for how to address the problem.