Stress, mitochondrial dysfunction, and inflammation are key pathophysiological processes contributing to neuroprogression in mental illness. These factors independently and collectively impact critical cellular mechanisms essential for healthy brain development and function. As these damaging processes continue, cellular debris (damaged DNA and proteins) accumulates, and neuronal integrity is impaired. In addition to this, the myelin sheath that encapsulates neurones to enable smooth and efficient communication throughout the brain is impaired. This chapter outlines how these factors are impacted by stress, inflammation, and mitochondrial function and how they work independently, and together, to increase risk for the development of mental illness, as well as to promote neuroprogression of the illness over time. We discuss how targeting these pathophysiological processes through interdependent factors such as the NLRP3 inflammasome, which sits at the intersection of these mechanistic pathways, may unlock opportunities to limit neuroprogression in the future.