Significance High-risk neuroblastoma accounts for nearly 15% of all pediatric cancer-related deaths. MYCN is an oncogene amplified in roughly half of high-risk neuroblastoma cases and finding new therapies to neutralize MYCN is a high priority for pediatric cancer. Here we demonstrate that MYCN -amplified neuroblastomas are sensitive to the combined inhibition of MCT1 and complex I of the mitochondrion. Sensitivity is due to low expression of MCT4 and high expression of MCT1 and the MCT1 chaperone CD147. Pharmacologic inhibition with AZD3965 and phenformin leads to complementary inhibition of metabolic processes that ultimately leads to cell death.