Each year, at least 1.7 million Americans develop sepsis (previously ‘severe sepsis’), of which 270,000 will die. Globally sepsis afflicts 19 million people and incurs 5 million deaths. In the US, it is present in 6% of adult hospitalizations and causes 1 in 3 in-hospital deaths. With a case fatality rate of 15.6%, it is the 10th leading cause of death. But even after clinical resolution of their infection, and long after we discharge them from the hospital, these patients are not ‘cured.’ The long-term mortality is upwards of 9 times higher after treatment for community acquired pneumonia and higher than mortality after an initial hospitalization for heart failure, stroke or major fracture. Two- and 5-year mortality among individuals who had sustained sepsis were 28.8% and 43.8% compared with death rates of 2.6% and 8.3% among those who never developed sepsis. And this elevated risk is not explained by a higher burden of chronic diseases prior to the occurrence of infection. No, these people are on a different biological trajectory characterized by an elevated risk of death. We now show that sepsis induces a durable restructuring of the complex machinery regulating mitochondrial and cellular Ca2+ homeostasis that fundamentally alters the future phenotype and fate of the cell. These changes persist long after clinical resolution of sepsis and lead to profound alterations in Ca2+ signaling, oxidative metabolism, and the sensitivity to Ca2+-dependent cell death pathways. These post-sepsis changes underlie the elevated risk of long-term death observed in survivors. Yet, they can be modulated to offer a personalized approach to realign these biological trajectories to a more adaptive, healthy phenotype.