An important role for bioenergetic dysfunction is increasingly emerging to potentially explain the paradox of clinical and biochemical organ failure in sepsis yet minimal cell death, maintained tissue oxygenation and recovery in survivors. Associations are well-recognized between the degree of mitochondrial dysfunction and outcomes. While this does not confirm cause-and-effect, it does nevertheless suggest a new route for therapeutic intervention focused on either mitochondrial protection or acceleration of the recovery process through stimulation of mitochondrial biogenesis (new protein turnover). This is particularly pertinent in light of the multiple trial failures related to immunomodulatory therapies. This overview will provide insights into mitochondrial biology, the relevance to sepsis, and therapeutic opportunities that possibly emerge.