Older residents of long-term care facilities (LTCFs), also known as nursing homes, care homes, or residential aged care facilities, often have multiple health conditions and are exposed to polypharmacy. Use of high-risk medications such as opioids, glucose-lowering medications, antithrombotics, and antipsychotics is prevalent among residents of LTCFs. Ensuring appropriate use of high-risk medications is important to minimize the risk of medication-related harm in this vulnerable population. This paper provides an overview of the prevalence and factors associated with high-risk medication use among residents of LTCFs. Evidencebased strategies to optimize the use of high-risk medications and enhance resident outcomes are also discussed.