OBJECTIVES: Non-adherence to medications in patients with diabetes which results in poor clinical outcomes and increased healthcare cost is commonly reported globally. Factors associated with poor medication adherence have also been widely studied. However, interventions aimed at enhancing medication adherence have shown conflicting results with modest efficacy. These interventions usually target limited barriers, neglecting many other important factors. A clear and comprehensive conceptual framework that captures all possible factors has not been established. We aimed to develop a conceptual framework that addresses the complex network of barriers to medication adherence in patients with diabetes. METHODS: Fourteen databases and grey literature sources were systematically searched through April 2016. Systematic reviews reporting barriers to medication adherence in patients with diabetes were identified. A thematic approach was used to categorize all identified barriers from the reviews and to create a matrix representing the complex network and relations of the different barriers. RESULTS: Seventeen systematic reviews were used for the development of the conceptual framework. Overall, six different themes emerged: patient–, medication–, disease–, provider–, system–, and society–related factors. Each of these themes was further classified into different categories. It was noted that most interactions were identified to be within the patient-related factors, which not only interact with other themes but also within the same theme. Patient’s demographics as well as culture were the most notable factors in terms of interactions with other categories and themes. CONCLUSIONS: The intricate network and interactions identified between different themes and within individual themes indicate the complexity of the problem. This framework will enhance the understanding of the complex relation between different barriers and facilitate design of more useful interventions. Future interventions for enhancing adherence should look at the overall factors and target multiple themes of barriers in order to improve patient outcomes.