Individuals with serious mental illnesses such as psychosis still experience higher mortality rates than the general population, decades after data have linked the gap to increased rates of physical illness, delayed diagnosis, low treatment rates and worse outcomes from treatment received. The nature of the relationship between psychosis and comorbid physical illness is complex. Multiple strategies directed at different levels of disease process, health care systems and stakeholder culture are likely required to make sustained progress in reducing the mortality gap. Evidence for strategies that effectively reduce the burden of physical co-morbidity and lead to improved health outcomes are still in their infancy but growing at a reassuringly fast rate. This editorial considers the existing evidence base and makes suggestions for the development and future direction of this urgent research agenda and how this knowledge can be implemented in clinical practice.