Several studies have demonstrated clinical benefits of sustained cholinesterase inhibition with rivastigmine in Alzheimer's disease (AD) and Parkinson's disease dementia (PDD). Unlike donepezil and galantamine that selectively inhibit acetylcholinesterase (AChE; EC 184.108.40.206), rivastigmine is a unique cholinesterase inhibitor with both AChE and butyrylcholinesterase (BuChE; EC 220.127.116.11) inhibitory activity. Rivastigmine is also available as transdermal patch that has been approved by the US Food and Drug Administration for the treatment of mild, moderate, and severe AD as well as mild-to-moderate PDD. In this review, we explore the role of BuChE inhibition in addition to AChE inhibition with rivastigmine in the outcomes of cognition, global function, behavioral symptoms, and activities of daily living. Additionally, we review the evidence supporting the use of dual AChE-BuChE inhibitory activity of rivastigmine as a therapeutic strategy in the treatment of neurological disorders, with a focus on the role of rivastigmine in subcortical dementias such as vascular dementia (VaD) and PDD. Toward this objective, we performed a literature search in PubMed and Ovid with limits to articles published in the English language before June 2016. The available evidence from the literature suggests that the dual inhibition of AChE and BuChE may afford additional therapeutic potential of rivastigmine in subcortical dementias (subcortical VaD and PDD) with benefits on cognition and behavioral symptoms. Rivastigmine was found to specifically benefit executive dysfunction frequently observed in subcortical dementias; however, large randomized clinical studies are warranted to support these observations.