OBJECTIVE: To review the literature on strategies to optimize medication adherence in community-dwelling older adults and to make recommendations for clinical practice. METHODS: A systematic literature search was conducted using the MEDLINE, CINAHL, PsycINFO, International Pharmaceutical Abstracts, and EMBASE databases for randomized controlled trials examining strategies to optimize medication adherence in patients aged 65 or older prescribed long-term medication regimens. Additional studies were found by examining the reference lists of systematic reviews and selected papers. 34 papers reporting on 33 studies met the eligibility criteria and were included in this review. RESULTS: Improvement in adherence was mixed across the studies examining educational interventions, with only 12 of the 28 studies showing improvement in adherence; most were delivered by pharmacists. Effect sizes for the statistically significant educational interventions ranged from Cohen's d = 0.14 to 4.93. Four of the 5 interventions using memory aids and cues, some in conjunction with newer technologies, improved adherence. Effect sizes for the statistically significant interventions using memory aids and cues ranged from Cohen's d = 0.26 to 2.72. CONCLUSION: The evidence from this review does not clearly support one single intervention to optimize medication adherence in older patients. Future studies should explore suggestive strategies, such as tailored interventions involving ongoing contact, and should endeavor to correct methodologic weaknesses found in the literature.