Optimal cognitive functioning is necessary to successfully negotiate one's environment, yet medical conditions can interfere with brain health, thus negatively impacting cognitive functioning. Such comorbidities include hypertension, heart disease, diabetes, depression, and HIV, as well as others. The physiological properties of these comorbidities can reduce one's cognitive reserve and limit one's cognitive efficiency. This article provides an overview of a few common comorbidities known to affect cognitive functioning and addresses ways in which cognitive functioning may be ameliorated and protected or mitigated in lieu of cognitive declines in such clinical populations. Implications for nursing practice and research are posited.