The literature consistently shows that medical–surgical nurses frequently lack the knowledge, skills, and attitudes necessary to render holistic nursing care to patients with severe mental illness (SMI). The negative perceptions often portrayed by medical–surgical nurses towards SMI patients with comorbid medical–surgical disorders must be addressed in order to ameliorate treatment gaps. Current concepts, issues, and challenges associated with the perceptions of nurses who care for patients with (SMI) in medical–surgical settings can prove overwhelming to both nurses and patients, and can result in concerning practice gaps. In accordance with a contemporary model of patient-centered care, it is imperative that medical–surgical nurses acquire the knowledge, skills, and attitudes necessary to work with this high-risk population. Cultivating an environment that promotes apposite attitudes along with effective training programs for medical–surgical nurses, may shift negative perceptions and ultimately meet best practice standards and improve outcomes for patients with SMI.