Background: It is unclear as to which interventions are effective at improving medication adherence in individuals with serious and persistent mental illness. The goal of this systematic review is to synthesize evidence examining the effectiveness, harms, and costs of interventions to improve medication adherence in patients with psychotic spectrum disorders and bipolar disorder. Methods: We conducted a systematic search of several electronic databases through January 2015 using a structured search strategy. Studies were included if they involved adult patients in general mental health settings, reported both measures of medication adherence and clinical outcomes, and were of sufficient methodological rigor. Studies were quality assessed and synthesized using established methods. Results: We idented 24 studies that met inclusion criteria. Overall, 20 studies addressed interventions in patients with psychotic spectrum disorders. These interventions varied widely, with generally mixed findings contributing to low or insufficient strength of evidence; studies involving family members and technology interventions were the most consistently associated with a positive effect; however, the strength of the evidence was low because of intervention heterogeneity. The evidence was insufficient to determine the effectiveness of interventions in patients with bipolar disorder. Conclusions: In individuals with psychotic spectrum disorders, interventions with family members or technology had the most consistent positive effect on adherence, although replication with objective adherence measures along with evaluation of harms and costs is needed. There was insufficient evidence to draw conclusions about interventions in individuals with bipolar disorder.