The ability to define thresholds for the clinical significance (clinical importance) of outcome measures in dementia drug research is critical to determining the changes on outcome measures that patients and families would consider worth the cost and worth risking the side effects of medications (i.e., clinical importance is central to informed consent when starting such medications). Thresholds for clinical significance are also required for drug trial sample size calculation (if the studies are to be powered to detect clinically important difference) and for decisions regarding whether medications should be accepted on formularies and should be funded. To better understand what measures of clinical significance have been employed in dementia drug research, a systematic review was performed of double-blind randomized controlled trials (RCTs) of cholinesterase inhibitors and memantine in subjects with Alzheimer's disease, vascular dementia, mixed dementia, and mild cognitive impairment. Of the 57 dementia drug RCTs reviewed, only 46% discussed the clinical significance of their results. The most commonly cited measures of clinical significance were a 4-point change in the Alzheimer's Disease Assessment Scale--Cognitive Subscale and changes on global scales. The majority of measures of clinical significance were opinion based. Only one study empirically measured patient perspective regarding thresholds for clinical significance. Despite being central to the interpretation of trial results and to decisions regarding whether to employ trial findings in clinical practice, patient- and caregiver-centered measures of clinical significance have not been adequately studied and integrated into dementia drug RCTs. It is recommended that discussions of clinical importance receive greater emphasis in research standards published by organizations such as the CONSORT group (http://www.consort-statement.org). Drug formulary review committees and licensing agencies (e.g., U.S. Food and Drug Administration, European Agency for the Evaluation of Medicinal Products, Health Canada) should consider requiring an assessment of clinical significance of the drugs they review. To move this field forward, funding agencies should consider initiating requests for proposals focused on the determination of the minimally clinically important difference (MCID) of outcome measures employed in dementia research. Once empirical data on MCIDs are available, then these funding agencies should consider supporting a consensus conference to review and select the optimal measures of clinical importance in dementia research. A preliminary organizational framework of measures of clinical significance is presented in this article to facilitate the work of such a consensus forum.