A recent observational study in a large cohort of critically ill patients confirms the association between hyperlactatemia and mortality. The mechanisms regulating the rates of lactate production and clearance in critical illness remain poorly understood. During exercise, hyperlactatemia clearly results from an imbalance between oxygen delivery and energy requirements. In critically ill patients, the genesis of hyperlactatemia is significantly more complex. Possible mechanisms include regional hypoperfusion, an inflammation-induced upregulation of the glycolitic flux, alterations in lactate-clearing mechanisms, and increases in the work of breathing. Understanding how these complex processes interact to produce elevations in lactate continues to be an important area of research.