Current health care systems do not sufficiently address contributors, also known as modifiable behavior factors, to severe mental illnesses (SMI). Instead treatment is focused on decreasing symptom-experience rather than reducing the detrimental effect of biological predisposition and behavioral influences on illness. Health care services and patients alike call for a more comprehensive, individual approach to mental health care, especially for people with SMI. A Syndemics framework has been previously used to identify ecological and social contributors to an HIV epidemic in the 1990s, and the same framework is transferable to mental health research to identify the relationship between contributing factors and the outcomes of SMI. Using this approach, a holistic insight into mental illness experience could inform more effective health care strategies that lessen the burden of disease on people with SMI. In this review, the components of a Syndemic framework, the scientific contributions to the topic so far, and the possible future of mental health research under the implementation of a Syndemic framework approach are examined.