The mitochondrial pyruvate oxidation route is a tightly regulated process, which is essential for aerobic cellular energy production. Disruption of this pathway may lead to severe neurometabolic disorders with onset in early childhood. A frequent finding in these patients is acute and chronic lactic acidemia, which is caused by increased conversion of pyruvate via the enzyme lactate dehydrogenase. Under stable clinical conditions, this process may remain well compensated and does not require specific therapy. However, especially in situations with altered energy demands, such as febrile infections or longer periods of fasting, children with mitochondrial disorders have a high risk of metabolic decompensation with exacerbation of hyperlactatemia and severe metabolic acidosis. Unfortunately, no controlled studies regarding therapy of this critical condition are available and clinical outcome is often unfavorable. Therefore, the aim of this review was to formulate expert-based suggestions for treatment of these patients, including dietary recommendations, buffering strategies and specific drug therapy. However, it is important to keep in mind that a specific therapy for the underlying metabolic cause in children with mitochondrial diseases is usually not available and symptomatic therapy especially of severe lactic acidosis has its ethical limitations.