Abstract Diagnostic accuracy is the first step to proper treatment, management, and future planning in dementia. Diagnostic challenges arise due to the co-occurrence of a multitude of conditions that contribute to cognitive changes in aging. Improving differential diagnostic skills is critical for detection, intervention, and treatment, in addition to the reduction of harm associated with missed and misdiagnoses. This chapter reviews differential diagnosis between the three main categories of conditions known to promote cognitive impairment in older adults and mimic neurodegenerative conditions: delirium; medical conditions; and psychiatric conditions. In addition, a framework is provided to assist the clinician broadly in making a differential diagnosis.