Mindfulness-based therapy (MBT) has gained attention in recent years as a promising treatment for patients with schizophrenia for whom traditional interventions are not effective. Research demonstrates improvements in psychotic symptoms, emotion regulation, and other areas including re-hospitalization rates and insight into illness following MBT interventions. Yet MBT studies have not carefully reported results in patients with schizophrenia and co-occurring substance use or comorbid medical problems, bringing into question the generalizability of these findings. This narrative review explores the literature regarding the use of mindfulness-based interventions for patients with schizophrenia as well as for patients with substance use disorder, cardiovascular disease, obesity, and diabetes. Findings suggest that MBTs can improve craving in substance use disorder, eating related behaviors in obesity, diabetes-related distress, and metabolic regulation in patients with diabetes. Increased insula and anterior cingulate cortex volumes and activities following MBTs might be associated with the potential benefit of MBTs in patients with schizophrenia. Our review provides a foundational basis in support of the need for future studies evaluating the safety and efficacy of MBTs for schizophrenia with co-occurring substance use disorder and/or comorbid cardiometabolic problems.