Metabolic adaptations play a key role in fueling tumor growth. However, less is known regarding the metabolic changes that promote cancer progression to metastatic disease. Herein, we reveal that breast cancer cells that preferentially metastasize to the lung or bone display relatively high expression of PGC-1α compared with those that metastasize to the liver. PGC-1α promotes breast cancer cell migration and invasion in vitro and augments lung metastasis in vivo. Pro-metastatic capabilities of PGC-1α are linked to enhanced global bioenergetic capacity, facilitating the ability to cope with bioenergetic disruptors like biguanides. Indeed, biguanides fail to mitigate the PGC-1α-dependent lung metastatic phenotype and PGC-1α confers resistance to stepwise increases in metformin concentration. Overall, our results reveal that PGC-1α stimulates bioenergetic potential, which promotes breast cancer metastasis and facilitates adaptation to metabolic drugs. Display omitted •PGC-1α expression is enriched in breast cancer cells that metastasize to lung and bone•PGC-1α functionally promotes breast cancer metastasis•PGC-1α augments global bioenergetic capacity•PGC-1α confers resistance to bioenergetic disruptors Andrzejewski et al. show that PGC-1α promotes breast cancer metastasis and increases global bioenergetic capacity, which enables breast cancer cells to overcome the metabolically demanding metastatic process. Cancer cells with elevated PGC-1α activity are resistant to bioenergetic disruptors, such as metformin.